Inhibitors of influenza viruses replication

ABSTRACT

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A compound is represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2010/038988, filed Jun. 17, 2010 which claims priority to U.S.Provisional Application No. 61/187,713, filed on Jun. 17, 2009, and toU.S. Provisional Application No. 61/287,781, filed on Dec. 18, 2009. Theentire teachings of these applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Influenza spreads around the world in seasonal epidemics, resulting inthe deaths of hundreds of thousands annually—millions in pandemic years.For example, three influenza pandemics occurred in the 20th century andkilled tens of millions of people, with each of these pandemics beingcaused by the appearance of a new strain of the virus in humans. Often,these new strains result from the spread of an existing influenza virusto humans from other animal species.

Influenza is primarily transmitted from person to person via largevirus-laden droplets that are generated when infected persons cough orsneeze; these large droplets can then settle on the mucosal surfaces ofthe upper respiratory tracts of susceptible individuals who are near(e.g. within about 6 feet) infected persons. Transmission might alsooccur through direct contact or indirect contact with respiratorysecretions, such as touching surfaces contaminated with influenza virusand then touching the eyes, nose or mouth. Adults might be able tospread influenza to others from 1 day before getting symptoms toapproximately 5 days after symptoms start. Young children and personswith weakened immune systems might be infectious for 10 or more daysafter onset of symptoms.

Influenza viruses are RNA viruses of the family Orthomyxoviridae, whichcomprises five genera: Influenza virus A, Influenza virus B, Influenzavirus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wildaquatic birds are the natural hosts for a large variety of influenza A.Occasionally, viruses are transmitted to other species and may thencause devastating outbreaks in domestic poultry or give rise to humaninfluenza pandemics. The type A viruses are the most virulent humanpathogens among the three influenza types and cause the most severedisease. The influenza A virus can be subdivided into differentserotypes based on the antibody response to these viruses. The serotypesthat have been confirmed in humans, ordered by the number of known humanpandemic deaths, are: H₁N1 (which caused Spanish influenza in 1918),H₂N2 (which caused Asian Influenza in 1957), H₃N2 (which caused HongKong Flu in 1968), H₅N1 (a pandemic threat in the 2007-08 influenzaseason), H₇N7 (which has unusual zoonotic potential), H₁N2 (endemic inhumans and pigs), H₉N2, H₇N2 , H₇N3 and H₁₀N7.

The Influenza virus B genus has one species, influenza B virus.Influenza B almost exclusively infects humans and is less common thaninfluenza A. The only other animal known to be susceptible to influenzaB infection is the seal. This type of influenza mutates at a rate 2-3times slower than type A and consequently is less genetically diverse,with only one influenza B serotype. As a result of this lack ofantigenic diversity, a degree of immunity to influenza B is usuallyacquired at an early age. However, influenza B mutates enough thatlasting immunity is not possible. This reduced rate of antigenic change,combined with its limited host range (inhibiting cross species antigenicshift), ensures that pandemics of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, whichinfects humans and pigs and can cause severe illness and localepidemics. However, influenza C is less common than the other types andusually seems to cause mild disease in children.

Influenza A, B and C viruses are very similar in structure. The virusparticle is 80-120 nanometers in diameter and usually roughly spherical,although filamentous forms can occur. Unusually for a virus, its genomeis not a single piece of nucleic acid; instead, it contains seven oreight pieces of segmented negative-sense RNA. The Influenza A genomeencodes 11 proteins: hemagglutinin (HA), neuraminidase (NA),nucleoprotein (NP), M1, M2, NS_(1,) NS₂(NEP), PA, PB1, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles.HA is a lectin that mediates binding of the virus to target cells andentry of the viral genome into the target cell, while NA is involved inthe release of progeny virus from infected cells, by cleaving sugarsthat bind the mature viral particles. Thus, these proteins have beentargets for antiviral drugs. Furthermore, they are antigens to whichantibodies can be raised. Influenza A viruses are classified intosubtypes based on antibody responses to HA and NA, forming the basis ofthe H and N distinctions (vide supra) in, for example, H₅N1.

Influenza produces direct costs due to lost productivity and associatedmedical treatment, as well as indirect costs of preventative measures.In the United States, influenza is responsible for a total cost of over$10 billion per year, while it has been estimated that a future pandemiccould cause hundreds of billions of dollars in direct and indirectcosts. Preventative costs are also high. Governments worldwide havespent billions of U.S. dollars preparing and planning for a potentialH₅N1 avian influenza pandemic, with costs associated with purchasingdrugs and vaccines as well as developing disaster drills and strategiesfor improved border controls.

Current treatment options for influenza include vaccination, andchemotherapy or chemoprophylaxis with anti-viral medications.Vaccination against influenza with an influenza vaccine is oftenrecommended for high-risk groups, such as children and the elderly, orin people that have asthma, diabetes, or heart disease. However, it ispossible to get vaccinated and still get influenza. The vaccine isreformulated each season for a few specific influenza strains but cannotpossibly include all the strains actively infecting people in the worldfor that season. It takes about six months for the manufacturers toformulate and produce the millions of doses required to deal with theseasonal epidemics; occasionally, a new or overlooked strain becomesprominent during that time and infects people although they have beenvaccinated (as by the H₃N2 Fujian flu in the 2003-2004 influenzaseason). It is also possible to get infected just before vaccination andget sick with the very strain that the vaccine is supposed to prevent,as the vaccine takes about two weeks to become effective.

Further, the effectiveness of these influenza vaccines is variable. Dueto the high mutation rate of the virus, a particular influenza vaccineusually confers protection for no more than a few years. A vaccineformulated for one year may be ineffective in the following year, sincethe influenza virus changes rapidly over time, and different strainsbecome dominant.

Also, because of the absence of RNA proofreading enzymes, theRNA-dependent RNA polymerase of influenza vRNA makes a single nucleotideinsertion error roughly every 10 thousand nucleotides, which is theapproximate length of the influenza vRNA. Hence, nearly everynewly-manufactured influenza virus is a mutant—antigenic drift. Theseparation of the genome into eight separate segments of vRNA allowsmixing or reassortment of vRNAs if more than one viral line has infecteda single cell. The resulting rapid change in viral genetics producesantigenic shifts and allows the virus to infect new host species andquickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidaseinhibitors being particularly effective, but viruses can developresistance to the standard antiviral drugs.

Thus, there is still a need for drugs for treating influenza infections,such as for drugs with expanded treatment window, and/or reducedsensitivity to viral titer.

SUMMARY OF THE INVENTION

The present invention generally relates to methods of treatinginfluenza, to methods of inhibiting the replication of influenzaviruses, to methods of reducing the amount of influenza viruses, tocompounds and compositions that can be employed for such methods.

In one aspect, the present invention is directed to a method ofinhibiting the replication of influenza viruses in a biological sampleor in a patient. In one embodiment, the method comprises administeringto said biological sample or patient an effective amount of a compoundrepresented by Structural Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein:

Z¹ is —R*, —F, —Cl, —CN, —OR*, —CO₂R*, —NO₂, or —CON(R*)₂;

Z² is —R*, —OR*, —CO₂R*, —NR*₂, or —CON(R*)₂;

Z³ is ——H, —O—H, halogen (e.g., —Cl or —Br), —NH₂; —NH(C₁C₄ alkyl);—N(C₁-C₄ alkyl)₂, —O(C₁C₄ alkyl), or C₁C₆ alkyl that is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, and —O(C₁C₄ alkyl);

R¹ is H or C₁C₆ alkyl;

R² is —H; —F; —NH₂; —NH(C₁C₄ alkyl); —N(C₁-C₄ alkyl)₂; C═N—OH;cyclopropyl that is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, —OCH₃, and CH₃; or C₁-C₄ alkyl that is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); and

R³ is ——H, Cl, —F, —O—H, —O(C₁-C₄ alkyl), —NH₂, NH(C₁C₄ alkyl), —N(C₁-C₄alkyl)₂, —Br, CN, or C₁-C₄ aliphatic that is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, —NH₂, -NH(C₁C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy;

R⁴ is:

wherein ring T is a C₃-C₁₀ non-aromatic carbocycle optionallysubstituted with one or more instances of J^(A), or a 3-10 memberednon-aromatic heterocycle optionally substituted with one or moreinstances of J^(B), or ring T and R⁹ optionally form a non-aromaticC₅C₁₀ membered carbocycle optionally substituted with one or moreinstances of J^(A) or 5-10 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(B) ;

wherein ring J is a 3-10 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(B); or

wherein ring D is a 4-10 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1); and

each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, —NCO, and Q¹—R⁵; or optionally twoJ^(A) and two J^(B), respectively, together with the atom(s) to whichthey are attached, independently form a 4-8 membered ring (e.g., spiroring or fused ring) that is optionally substituted with one or moreinstances of J^(E1);

Q¹ is independently a bond, —O—, —S—, —NR′—, —C(O)—, —C(═NR)—,—C(═NR)NR—, —NRC(═NR)NR—, —CO₂—, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂—, —OC(O)NR′—, —S(O)—,—SO₂—, —SO₂NR′—, —NRSO₂—, or —NRSO₂NR′—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, —CO₂SO₂—, or —(CR⁶R⁷)_(p)—Y¹—;

Y¹ is independently a bond, —O—, —S—, —NR′—, —C(O)—, —C(═NR)—,—C(═NR)NR—, —NRC(═NR)NR—, —CO₂—, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂—, —OC(O)NR′—, —S(O)—,—SO₂—, —SO₂NR′—, —NRSO₂—, —NRSO₂NR′—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, or —CO₂SO₂—;

R⁵ is: i) —H; ii) a C₁C₆ aliphatic group optionally substituted with oneor more instances of J^(C1); iii) a C₃-C₁₀ non-aromatic carbocycle, or a6-10 membered carbocyclic aryl group, each optionally and independentlysubstituted with one or more instances of J^(C1); or iv) a 4-10 memberednon-aromatic heterocycle, or a 5-10 membered heteroaryl group, eachoptionally and independently substituted with one or more instances ofJ^(D1); or

R⁵, together with Q¹, optionally forms a 4-8 membered, non-aromatic ringoptionally substituted with one or more instances of J^(E1); and

R⁶ and R⁷ are each independently —H or C₁C₆ alkyl optionally substitutedwith one or more substitutents selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁C₆ alkoxy, C₁C₆haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆ cyanoalkoxy, C₁C₆ hydroxyalkoxy andC₂-C₆ alkoxyalkoxy, or optionally R⁶ and R⁷, together with the carbonatom to which they are attached, form a cyclopropane ring optionallysubstituted with one or more instances of methyl;

R⁹ is independently ——H, halogen, cyano, hydroxy, amino, carboxy, C₁C₆alkyl, C₁C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl, C₁C₆ alkoxy, C₁C₆haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆ cyanoalkoxy, C₁C₆ hydroxyalkoxy andC₂-C₆ alkoxyalkoxy;

R¹³ and R¹⁴ are each independently ——H, halogen, or C₁C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁C₆ alkoxy, C₁C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆cyanoalkoxy, C₁C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy;

optionally, R¹³ and R¹⁴, together with the carbon atom to which they areattached, form a cyclopropane ring optionally substituted with one ormore instances of methyl;

R and R′ are each independently —H or C₁C₆ alkyl optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,amino, carboxy, C₁C₆ alkoxy, C₁C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆cyanoalkoxy, C₁C₆ hydroxyalkoxy and C₂-C₆ alkoxyalkoxy; or optionallyR′, together with R⁵ and the nitrogen atom to which they are attached,forms a 5-7 membered non-aromatic heterocycle optionally substitutedwith one or more instances of J^(D1);

R* is independently: i) —H; ii) a C₁C₆ alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₃-C₈ non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle,phenyl, 5-6 membered heteroaryl, —O(C₁C₆ alkyl), and C(O)(C₁-C₆—alkyl);wherein each of said alkyl groups in —O(C₁C₆ alkyl), andC(O)(C₁-C₆—alkyl) is optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁C₄ alkyl), CO(C₁C₄ alkyl), CO₂H, CO₂(C₁C₄ alkyl), and C₁C₄alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, andheteroaryl is independently and optionally substituted with one or moreinstances of J^(E1); or iii) a C₃-C₈ non-aromatic carbocycle, or a 4-8membered non-aromatic heterocycle, each of which is independently andoptionally substituted with one or more instances of J^(E1); and

each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), —C(O)R^(b), C(═NR)NR^(c), C(═NR)NR^(b)R^(c),—NRC(═NR)NR^(b)R^(c), C(O)OR^(b), —OC(O)R^(b), —NRC(O)R^(b),C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b), —OCONR^(b)R^(c),C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)), —SO₂NR^(c)R^(b),—NRSO₂R^(b), —NRSO₂NR^(c)R^(b), —P(O)(OR^(a))₂, —OP(O)(Or^(a))₂,—P(O)₂OR^(a) and CO₂SO₂R^(b), or optionally, two J^(C1) and two J^(D1),respectively, together with the atom(s) to which they are attached,independently form a 4-8-membered ring that is optionally substitutedwith one or more instances of J^(E1);

each J^(E1) is independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, amido, C₁C₆ alkyl, —O(C₁C₆alkyl), and C(O)(C₁-C₆—alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁C₄ alkyl),CO(C₁C₄ alkyl), CO₂H, CO₂(C₁C₄ alkyl), and C₁C₄ alkoxy; and

R^(a) is independently: i) a C₁C₆ aliphatic group optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido,—O(C₁C₆ alkyl), C(O)(C₁-C₆—alkyl), C₃-C₈ non-aromatic carbocycle, 4-8membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and6-10 membered carbocyclic aryl group; wherein each of said alkyl groupsfor the substituents of the C₁C₆ aliphatic group represented by R^(a) isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁C₄ alkyl),CO(C₁C₄ alkyl), CO₂H, CO₂(C₁C₄ alkyl), and C₁C₄ alkoxy; and wherein eachof said carbocycle, heterocycle, heteroaryl and carbocyclic aryl groupsfor the substituents of the C₁C₆ aliphatic group represented by R^(a) isoptionally and independently substituted with one or more instances ofJ^(E1);

ii) a C₃-C₈ non-aromatic carbocycle, or a 4-8 membered non-aromaticheterocycle, each of which is optionally and independently substitutedwith one or more instances of J^(E1); or

iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic arylgroup, each of which is optionally and independently substituted withone or more instances of J^(E1); and

R^(b) and R^(c) are each independently R^(a) or —H; or optionally, R^(b)and R^(c), together with the nitrogen atom(s) to which they areattached, each independently form a 5-7 membered non-aromaticheterocycle optionally substituted with one or more instances of J^(E1);

p is independently 1, 2, 3 or 4;

t is 0, 1 or 2;

j is 1 or 2; and

z is 1 or 2.

In another embodiment, the method comprises administering to saidbiological sample or patient an effective amount of a compoundrepresented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H;

R² is ——H, CH₃, —NH₂, —NH(C₁C₄ alkyl), or —N(C₁-C₄ alkyl)₂;

R⁴ is: i) a C₃-C₁₀ non-aromatic carbocycle optionally substituted withone or more instances of J^(A); ii) a 4-10 membered non-aromaticheterocycle optionally substituted with one or more instances of J^(B);or iii) a C₁C₆ aliphatic group optionally substituted with one or moresubstituents independently selected from the group consisting of J^(C);a C₃-C₈ non-aromatic carbocycle, or a 6-10 membered carbocyclic arylgroup, each optionally and independently substituted with one or moreinstances of J^(A); and a 5-10 membered heteroaryl group, or a 4-10membered non-aromatic heterocycle, each optionally and independentlysubstituted with one or more instances of J^(B);

each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, —NCO, and Q¹—R⁵; or optionally twoJ^(A) and two J^(B), respectively, together with the atom(s) to whichthey are attached, independently form a 5-7 membered ring that isoptionally substituted with one or more instanced of J^(E1);

J^(C) is independently selected from the group consisting of halogen,cyano, oxo, —OR⁵, —SR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵, C(O)NR′R⁵,C(O)NRC(O)OR⁵, —NRC(O)NRC(O)OR⁵, —NRC(O)R⁵, —NRC(O)NR′R⁵, —NRCO₂R⁵,—OC(O)NR′R⁵, —S(O)R⁵, —SO₂R⁵, —SO₂NR′R⁵, —NRSO₂R⁵, and —NRSO₂NR′R⁵;

Q¹ is independently a bond, —O—, —S—, —NR′—, C(O)—, C(═NR)—, CO₂—,—OC(O)—, C(O)NR′—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂—, —OC(O)NR′—, —S(O)—, —SO₂—, —SO₂NR′—, —NRSO₂—, or —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—;

Y¹ is independently a bond, —O—, —S—, —NR′—, C(O)—, C(═NR)—, CO₂—,—OC(O)—, C(O)NR′—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂—, —OC(O)NR′—, —S(O)—, —SO₂—, —SO₂NR′—, —NRSO₂—, or —NRSO₂NR′—;

R⁵ is: i) —H; ii) a C₁C₆ aliphatic group optionally substituted with oneor more instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycle, or a6-10 membered carbocyclic aryl group, each optionally and independentlysubstituted with one or more instances of J^(C1); or iv) a 4-8 memberednon-aromatic heterocycle, or a 5-10 membered heteroaryl group, eachoptionally and independently substituted with one or more instances ofJ^(D1). Optionally, R⁵, together with Q¹, optionally forms a 5-7membered, non-aromatic ring optionally substituted with one or moreinstances of J^(E1);

each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b),—NRC(O)R^(b), C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b),—OCONR^(b)R^(c), C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), —NRSO₂NR^(c)R^(b), and —P(O)(OR^(a))₂—, oroptionally, two J^(C1) and two J^(A1), respectively, together with theatoms to which they are attached, independently form a 5-7-membered ringthat is optionally substituted with one or more instances of J^(E1), andfused to the respective ring to which they are attached; and

each of Z¹, Z² , R³, R⁶, R⁷, R, R′,R*, J^(E1), R^(a), R^(b), R^(c) and pis independently as described above for Structural Formula (IA).

In another embodiment, the present invention is directed to a method ofreducing the amount of influenza viruses in a biological sample or in apatient. The method comprises administering to said biological sample orpatient an effective amount of a compound represented by StructuralFormula (I) or Structural Formula (IA), each and independently asdescribed above.

In yet another embodiment, the present invention is directed to a methodof treating or preventing influenza in a patient, comprisingadministering to said patient an effective amount of a compoundrepresented by Structural Formula (I) or Structural Formula (IA), eachand independently as described above.

In yet another embodiment, the present invention is directed to acompound represented by Structural Formula (IA) or a pharmaceuticallyacceptable salt thereof, wherein:

R¹ is ——H, C₁C₆ alkyl, S(O)₂—R″, or C(O)OR″; or alternatively R¹ is —Hor Ci₁C₆ alkyl;

R⁴ is:

wherein:

ring A is a C₃-C₁₀ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A), or heterocyleoptionally further substituted with one or more instances of J^(B);

rings B and C are each independently a 4-10 membered, non-aromaticheterocycle optionally and independently further substituted with one ormore instances of J^(B);

ring D is a 4-10 membered, non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1); or

ring A and R⁸ optionally form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, or ring A and R⁹ optionally form anon-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ringA and R¹¹ optionally form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, wherein each carbocycle is optionally furthersubstituted with one or more instances of J^(A), and wherein eachheteroocycle is optionally further substituted with one or moreinstances of J^(B); and

Q² is independently a bond, —O—, —S—, —NR—, C(O)—, C(═NR)—, C(═NR)NR—,—NRC(═NR)NR—, CO₂—, —OC(O)—, C(O)NR—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—,—NRC(O)—, —NRC(O)NR—, —NRCO₂—, —OC(O)NR—, —S(O)—, —SO₂—, —N(R)SO₂—,—SO₂N(R)—, —NRSO₂NR—, —P(O)(OR)O—, —OP(O)(OR^(a))O—, —P(O)₂O—, CO₂SO₂—,or —(CR⁶R⁷)_(p)—Y¹—;

Q³ is independently a bond, C(O)—, C(═NR)—, C(═NR)NR—, —NRC(═NR)NR—,CO₂—, C(O)NR—, —SO₂—, —SO₂N(R)—, C(O)NRC(O)O— or —(CR⁶R⁷)_(p)—Y¹—.

R″ is independently: i) a C₁-C₆—alkyl optionally substituted with one ormore substituents selected independently from the group consisting ofhalogen, cyano, hydroxyl, —NH₂, —NH(C₁C₆ alkyl), —N(C₁- C₆ alkyl)₂, C₁C₆alkoxy, C₁C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆ cyanoalkoxy, C₁C₆hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or ii) a C₃C₆ carbocyclic group,a 5-6 membered heteroaryl group, or a phenyl group, each optionally andindependently being substituted with one ore more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, nitro, —NH₂, —NH(C₁C₆ alkyl), —N(C₁C₆ alkyl)₂, C₁-C₆alkyl, C₁-C₆ halo alkyl, C₁C₆ cyano alkyl, C₁-C₆ —hydroxyalkyl,C₂C₆—alkoxyalkyl, C₁-C₆—aminoalkyl, C₁C₆ alkoxy, C₁C₆ haloalkoxy, C₁C₆aminoalkoxy, C₁C₆ cyanoalkoxy, C₁-C₆—hydroxyalkoxy, and C₂-C₆alkoxyalkoxy;

_(each of Z) ¹, Z², Z³, Q¹, Q², Q³, Y¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R, R′, R*, J^(A), J^(B), J^(C1), J^(D1), J^(E1),R^(a), R^(b), R^(c) and p is independently as described above forStructural Formula (IA) for the method of inhibiting the replication ofinfluenza viruses;

n and m are each independently 0 or 1 when rings A and B are3-6-membered; or n and m are each independently 0, 1 or 2 when rings Aand B are 7-10-membered;

k is 0, 1 or 2;

x and y are each independently 0, 1 or 2;

z is 1 or 2; and

provided that if Y¹ is a bond, then R⁵ is neither —H nor a C₁C₆aliphatic group; and

provided that if each Q² and Q³ independently is a bond, then R⁵ isneither —H nor a C₁C₆ aliphatic group.

In yet another embodiment, the present invention is directed to acompound represented by Structural Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein: the values of the variables ofStructural Formula (I) are as described below:

R¹ is ——H, C₁C₆ alkyl, S(O)₂—R″, or —(O)OR″; or alternatively R¹ is —Hor C₁C₆ alkyl.

R⁴ is:

ring A is a C₃-C₈ non-aromatic carbocycle optionally further substitutedwith one or more instances of J^(A), or heterocycle optionally furthersubstituedd with one or more instances of J^(B);

rings B and C are each independently a 4-8 membered, non-aromaticheterocycle optionally and independently further substituted with one ormore instances of J^(B);

ring D is a 4-8 membered, non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1);

R″ is independently: i) a C₁-C₆—alkyl optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxyl, -NH₂, —NH(C₁C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁C₆alkoxy, C₁C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆ cyanoalkoxy, C₁C₆hydroxyalkoxy and C₂-C₆ alkoxyalkoxy; or ii) a C₃C₆ carbocyclic group,5-6 membered heteroaryl group, or phenyl group, each optionally andindependently being substituted with one ore more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, nitro, —NH₂, —NH(C₁C₆ alkyl), —N(C₁C₆ alkyl)₂, C₁C₆ alkyl,C₁C₆ haloalkyl, C₁C₆ cyanoalkyl, C₁-C₆—hydroxyalkyl, C₂-C₆—alkoxyalkyl,C₁-C₆—aminoalkyl, C₁C₆ alkoxy, C₁C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁C₆cyanoalkoxy, C₁C₆—hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy;

each of Z¹, Z², Q¹, Q², Q³, Y¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R, R′, R*, J^(C1), J^(D1), J^(E1), R^(a), R^(b), R^(c)and p is independently as described above for Structural Formula (I) forthe method of inhibiting the replication of influenza viruses;

n and m are each independently 0 or 1 when rings A and B are4-6-membered; or n and m are each independently 0, 1 or 2 when rings Aand B are 7-8 membered;

k is 0, 1 or 2;

x and y are each independently 0, 1 or 2;

z is 1 or 2;

provided that if Y¹ is a bond, then R⁵ is neither —H nor anunsubstituted C₁C₆ aliphatic group; and

provided that if each Q² and Q³ independently is a bond, then R⁵ isneither —H nor a C₁C₆ aliphatic group.

In yet another embodiment, the present invention is directed to apharmaceutical composition comprising a compound represented byStructural Formula (I) or Structural Formula (IA), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant or vehicle, wherein the values of the variable of StructuralFormulae (I) and (IA) are each and independently as described above forthe compounds of the invention.

The present invention also provides use of a compound described hereinfor inhibiting the replication of influenza viruses in a biologicalsample or patient, for reducing the amount of influenza viruses in abiological sample or patient, or for treating influenza in a patient.

Also provided herein is use of a compound described herein for themanufacture of a medicament for treating influenza in a patient, forreducing the amount of influenza viruses in a biological sample or in apatient, or for inhibiting the replication of influenza viruses in abiological sample or patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing percentages of survial of Balb/c mice (4-5weeks of age) over time for a prophylaxis study in which an initial doseof Compound 514 (100 mg/kg) or vehicle only (0.5% Methylcellulose/0.5%Tween 80) were administered 2 hours prior to infection by oral gavage(10 mL/kg) and continued twice daily for 5 days.

FIG. 2 is a graph showing percentages of survial of Balb/c mice (4-5weeks of age) over time for a therapeutic treatment study in whichCompound 588 (200 mg/kg) or vehicle only were administered by oralgavage 24 hours post infection and continued twice daily for 10 days.

FIGS. 3-8 are tables showing some specific compounds of the invention.

DETAILED DECRIPTION OF THE INVENTION Uses of Disclosed Compounds

One aspect of the present invention is generally related to the use ofthe compounds described herein or pharmaceutically acceptable salts, orpharmaceutically acceptable compositions comprising such a compound or apharmaceutically acceptable salt thereof, for inhibiting the replicationof influenza viruses in a biological sample or in a patient, forreducing the amount of influenza viruses (reducing viral titer) in abiological sample or in a patient, and for treating influenza in apatient.

In one embodiment, the present invention is generally related to the useof compounds represented by Structural Formula (I) or Structural Formula(IA), or pharmaceutically acceptable salts thereof for any of the usesspecified above:

A first set of variables of Structural Formulae (I) and (IA) isindependently as follows:

Z¹ is —R*, —F, Cl, CN, —OR*, CO₂R*, —NO₂, or CON(R*)₂. Specifically, Z¹is ——H, C₁C₆ alkyl, —O(C₁C₆ alkyl), —F, CN, CO₂H, CO₂(C₁C₆ alkyl),CONH₂, CONH(C₁C₆ alkyl), or CON(C₁-C₆ alkyl)₂, wherein each of saidalkyl groups (e.g., represented by C₁C₆ alkyl, —O(C₁C₆ alkyl), CO₂(C₁C₆alkyl), CONH(C₁C₆ alkyl), and CON(C₁-C₆ alkyl)₂) is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, —NH(C₁C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, Z¹ is——H, —F, Cl, C₁C₄ haloalkyl (e.g., CF₃), C₁-C₄ alkyl, CH₂NH₂, C(O)NH₂,C(O)NH(CH₃), C(O)N(CH₃)₂, —O(C₁-C₄ alkyl), or CN. Specifically, Z¹ is——H, —F, Cl, CF₃, C₁-C₄ alkyl, or CN. Specifically, Z¹ is ——H, —F, Cl,CF₃, CH₃, or CN. Specifically, Z¹ is ——H, —F, or CN. Specifically, Z¹ is—H or —F.

Z² is —R*, —OR*, CO₂R*, —NR*₂, or CON(R*)₂. Specifically, Z² is ——H,C₁-C₆ alkyl, —O(C₁C₆ alkyl), —NH₂, —NH(C₁C₆ alkyl), or —N(C₁-C₆ alkyl)₂,wherein each of said alkyl groups (e.g., represented by C₁-C₆ alkyl,—O(C₁C₆ alkyl), —NH(C₁C₆ alkyl), and —N(C₁-C₆ alkyl)₂) is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, -NH(C₁C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, Z² is——H, C₁-C₆ alkyl, or —O(C₁-C₆ alkyl), wherein each of the alkyl groupsis optionally and independently substituted. Specifically, Z² is ——H, oran optionally substituted C₁-C₆ alkyl.

Z³ in Structural Formula (IA) is ——H, —O—H, halogen, —NH₂; —NH(C₁C₄alkyl); —N(C₁C₄ alkyl)₂, —O(C₁-C₄ alkyl), or C₁-C₆ alkyl that isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, and—O(C₁C₄ alkyl). Specifically, Z³ is ——H, —O(C₁C₄ alkyl), or C₁C₆ alkylthat is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁C₄ alkyl). Specifically, Z³ is —H or C₁C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, and—O(C₁C₄ alkyl). Specifically, Z³ is —H.

R¹ is —H or C₁₋₆ alkyl. Specifically, R¹ is —H.

R² is —H; —F; -NH₂; -NH(C₁C₄ alkyl); -N(C₁-C₄ alkyl)₂; C═N—OH;cyclopropyl that is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, —OCH₃, and CH₃; or C₁C₄ alkyl that is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, and —O(C₁C₄ alkyl). Specifically,R² is ——H, CH₃, -NH₂, -NH(C₁C₄ alkyl), or -N(C₁-C₄ alkyl)₂.Specifically, R² is ——H, —F, CH₃, CH₂O—H, or -NH₂. Specifically, R² is—H or CH₃.

R³ is ——H, Cl, —F, —O—H, —O(C₁C₄ alkyl), -NH₂, -NH(C₁C₄ alkyl), -N(C₁-C₄alkyl)₂, —Br, CN, or C₁C₄ aliphatic that is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁C₄ alkyl), CO(C₁C₄ CO₂H, CO₂(C₁C₄ alkyl), andC₁C₄ alkoxy. Specifically, R³ is ——H, Cl, —F, CF₃, —OCH₃, -NH₂,-NH(C₁C₄alkyl), -N(C₁-C₄ alkyl)₂, —Br, —O(C₁C₄ alkyl), CN, C₁-C₄haloalkyl, —O—H, or C₁C₄ aliphatic. Specifically, R³ is ——H, Cl, —F,CF₃, —OCH₃, -NH₂, -NH(C₁C₄alkyl), -N(C₁-C₄ alkyl)₂, —Br, —O(C₁-C₄alkyl), CHCH(CH₃), CHCH₂, CN, CH₂CF₃, —CH₂F, CHF₂, —O—H, or C₁-C₄ alkyl.Specifically, R³ is ——H, Cl, —F, —Br, CN, CF₃, —O(C₁C₄ alkyl), —O—H,-NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂. Specifically, R³ is ——H,—F, Cl, CF₃, -NH₂, -NH(CH₃), or —N(CH₃)₂. Specifically, R³ is ——H, Cl,or —F. Specifically, R³ is —Cl. Specifically, R³ is ——H, Cl, —F, —Br,CN, CF₃, CH₃, C₂H₅, —O(C₁-C₄ alkyl), —O—H, -NH₂, -NH(C₁C₄ alkyl), or-N(C₁-C₄ alkyl)₂. Specifically, R³ is ——H, —F, Cl, CF₃, CH₃, C₂H₅, -NH₂,-NH(CH₃), or —N(CH₃)₂. Specifically, R³ is —F or Cl.

R⁴ is: i) a C₃-C₁₀ non-aromatic carbocycle optionally substituted withone or more instances of J^(A); ii) a C₁-C₆ aliphatic group (e.g., C₁-C₆alkyl or C₂-C₆ alkenyl group) optionally substituted with one or moresubstituents independently selected from the group consisting of f; aC₃-C₈ non-aromatic carbocycle, or a 6-10 membered carbocyclic arylgroup, each optionally and independently substituted with one or moreinstances of J^(A); and a 5-10 membered heteroaryl group, or a 4-10membered non-aromatic heterocycle, each optionally and independentlysubstituted with one or more instances of J^(B); or iii) a 4-10 memberednon-aromatic heterocycle optionally substituted with one or moreinstances of J^(B). Specifically, R⁴ is i) an optionally substitutedC₃-C₁₀ carbocyclic ring; ii) a C₁-C₆ aliphatic group (e.g., C₁-C₆ alkylor C₂-C₆ alkenyl group) that is substituted with one or moresubstituents independently selected from the group consisting off, anoptionally substituted C₃-C₈ non-aromatic carbocycle, and an optionallysubstituted 4-10 membered non-aromatic heterocycle; or iii) anoptionally substituted, 4-10 membered non-aromatic heterocycle.Specifically, the C₁-C₆ aliphatic group represented by R⁴ is substitutedwith —OR⁵, —SR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵, C(O)NR′R⁵,C(O)NRC(O)OR⁵, —NRC(O)NRC(O)OR⁵, —NRC(O)R⁵, —NRC(O)NR′R⁵, —NRCO₂R⁵,—OC(O)NR′R⁵, —SOR⁵, —SO₂R⁵, —SO₂NR′R⁵, -N(R)SO₂R⁵, —NRSO₂NR′R⁵, anoptionally substituted C₃-C₈ non-aromatic carbocycle, and an optionallysubstituted 4-10 membered non-aromatic heterocycle.

More specifically, R⁴ is:

wherein ring T (including rings A, B and C described below) is a C₃-C₁₀non-aromatic carbocycle optionally substituted with one or moreinstances of J^(A), or a 3-10 membered non-aromatic heterocycleoptionally substituted with one or more instances of J^(B), or ring Tand R⁹ optionally form a non-aromatic C₅-C₁₀ membered carbocycleoptionally substituted with one or more instances of J^(A) or 5-10membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(B) ;

wherein ring J is a 3-10 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(B); or

wherein ring D is a 4-10 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1)). More specifically, R⁴is:

R⁵ is: i) H; ii) a C₁-C₆ aliphatic group optionally substituted with oneor more instances of J^(C1); iii) a C₃-C₁₀ non-aromatic carbocycle, or a6-10 membered carbocyclic aryl group, each optionally and independentlysubstituted with one or more instances of J^(C1); or iv) a 4-10 memberednon-aromatic heterocycle, or a 5-10 membered heteroaryl group, eachoptionally and independently substituted with one or more instances ofJ^(D1). Specifically, R⁵ is: i) —H; ii) a C₁-C₆ aliphatic group (e.g.,C₁-C₆ alkyl or C₂-C₆ alkenyl group) optionally substituted with one ormore instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycle, or a6-10 membered carbocyclic aryl group, each optionally and independentlysubstituted with one or more instances of J^(C1); or iv) a 4-8 memberednon-aromatic heterocycle, or a 5-10 membered heteroaryl group, eachoptionally and independently substituted with one or more instances ofJ^(D1). Optionally, R⁵, together with each of Q¹, Q² and Q³, optionallyand independently forms a 4-8 membered, non-aromatic ring optionallysubstituted with one or more instances of J^(E1). It is understood thatthe non-aromatic ring formed with R⁵ and Q¹ can employ a portion of Q¹.In some embodiments, R⁵, together with Q² and R⁸, optionally andindependently forms a 5-7 membered, non-aromatic ring optionallysubstituted with one or more instances of J^(E1).

Specifically, R⁵ is independently i) —H; ii) a C₁-C₆—alkyl orC₂-C₆—alkenyl group optionally substituted with one or more instances ofJ^(C1); iii) a C₃-C₈ non-aromatic carbocycle optionally substituted withone or more instances of J^(C1); iv) a phenyl group optionallysubstituted with one or more instances of J^(C1); v) a 4-8 memberednon-aromatic heterocycle optionally substituted with one or moreinstances of J^(D1); or vi) a 5-6 membered heteroaryl ring optionallysubstituted with one or more instances of J^(D1). Specifically, R⁵ isindependently i) —H; ii) a C₁-C₆—alkyl or C₂-C₆—alkenyl group optionallyand independently substituted with one or more instances of J^(C1); oriii) a 4-8 membered non-aromatic heterocycle optionally substituted withone or more instances of J^(D1). Specifically, R⁵ is independently i)—H; or ii) a C₁-C₆—alkyl or C₂-C₆—alkenyl group optionally andindependently substituted with one or more instances of J^(C1).

R⁶ and R⁷ are each independently —H or C₁-C₆ alkyl optionallysubstituted with one or more substitutents selected from the groupconsisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy, or optionally R⁶ and R⁷, togetherwith the carbon atom to which they are attached, form a cyclopropanering optionally substituted with one or more instances of methyl.Alternatively, R⁶ and R⁷ are each independently —H or C₁-C₄ alkyloptionally substituted with one or more substitutents selected from thegroup consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, C(O)O—H, —(CO)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy, or optionallyR⁶ and R⁷, together with the carbon atom to which they are attached,form a cyclopropane ring optionally substituted with one or moreinstances of methyl. Specifically, R⁶ and R⁷ are each independently —Hor CH₃, or, together with the carbon atoms to which they are attached,they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, amino, carboxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; or R⁸, together with Q² and R⁵, optionally andindependently forms a 5-7 membered, non-aromatic ring optionallysubstituted with one or more instances of J^(E1).

Each R⁹ is independently —H, halogen, cyano, hydroxy, amino, carboxy,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy; or R⁸, together with Q² and R⁵, optionally andindependently forms a 5-7 membered, non-aromatic ring optionallysubstituted with one or more instances of J^(E1). Specifically, each R⁹is independently ——H, halogen, cyano, hydroxy, amino, carboxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; or R⁸, together with Q² and R⁵, optionally andindependently forms a 5-7 membered, non-aromatic ring optionallysubstituted with one or more instances of J^(E1).

Optionally, R⁹ and ring T form a non-aromatic C₅C₁₀ membered carbocycleoptionally substituted with one or more instances of J^(A) or 5-10membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(B).

Specifically, each R⁸ is independently ——H, halogen, cyano, hydroxy,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂; and eachR⁹ is independently —H or C₁-C₄ alkyl, more specifically, ——H, CH₃, orCH₂CH₃.

R¹⁰ is independently —H; or a C₁-C₆ alkyl group optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆hydroxyalkoxy, C₂-C₆ alkoxyalkoxy, C₃-C₈ non-aromatic carbocycle,phenyl, a 4-8 membered non-aromatic heterocycle, and a 5-6 memberedheteroaryl group; wherein each of said carbocycle, phenyl, heterocycle,and heteroaryl group for the substituents of the C₁-C₆ alkyl grouprepresented by R¹⁰ is optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy. Specifically,R¹⁰ is independently ——H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆—alkoxyalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, or C₁-C₆cyanoalkyl. Specifically, R¹⁰ is —H or C₁-C₆—alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), andC₁-C₄ alkoxy. Specifically, R¹⁰ is —H or C₁-C₆—alkyl.

R¹¹, R¹², R¹³ and R¹⁴ are each independently ——H, halogen, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or optionally,R¹³ and R¹⁴ together with the carbon atom to which they are attachedform a cyclopropane ring, optionally substituted with one or moreinstances of methyl. Specifically, R¹¹ and R¹² are each independently —Hor C₁-C₄ alkyl; and R¹³ and R¹⁴ are each independently —H or C₁-C₄alkyl, or together with the carbon atoms to which they are attached,they form a cyclopropane ring. Specifically, R¹¹ and R¹² are eachindependently —H or CH₃; and R¹³ and R¹⁴ are each independently ——H,CH₃, or CH₂CH₃, or together with the carbon atoms to which they areattached, they form a cyclopropane ring. Optionally R¹¹ and ring A forma bridged ring optionally further substituted with one or more instancesof J^(A).

Ring A is a C₃-C₁₀ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A), or 3-10 memberednon-aromatic heterocycle optionally further substituted with one or moreinstances of J^(B). Specifically, ring A is an optionally substitutedC₃-C₈ non-aromatic carbocyclic or heterocyclic ring. Specifically, RingA is a C₃-C₈ non-aromatic carbocycle optionally further substituted withone or more instances of J^(A). Specifically, Ring A is a non-aromatic,4-7 or 5-7 membered, carbocyclic ring optionally further substitutedwith one or more instances of J^(A). A specific example of Ring A is anoptionally substituted, cyclohexyl or cyclopentyl ring.

Optionally, ring A and R⁸ form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, or ring A and R⁹ optionally form anon-aromatic, 5-10 membered, bridged carbocycle or heterocycle, ring Aand R¹¹ optionally form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, wherein each carbocycle is optionally furthersubstituted with one or more instances of J^(A), and wherein eachheteroocycle is optionally further substituted with one or moreinstances of J^(B). In some embodiments, the bridged rings are eachindependently 6-10 membered. Exemplary bridged rings include:

wherein each of rings G1-G4 is independently a 5-10 memberednon-aromatic bridged carbocycle optionally further substituted with oneor more instances of J^(A), and ring G5 is a 5-10 membered non-aromaticbridged heterocycle optionally further substituted with one or moreinstances of J^(B); R²¹, R²², R²³, R²⁴, and R²⁵ are each independently——H, halogen, —O—H, C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; X is —O—, —S—, or —NR^(g)—; R^(g)is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy; q is 0, 1 or 2; x is 0, 1 or 2; r is 1 or 2. Anadditional example of the bridged rings includes an adamantyl ring.

Ring B is a 4-10 membered, non-aromatic, heterocyclic ring that isoptionally further substituted with one or more instances of J^(B).Specifically, ring B is 4-8 membered. Specifically, ring B is 4-7 or 5-7membered. Specific examples of Ring B include:

wherein each of rings B1-B9 is optionally substituted.

Ring C is a 4-10 membered, non-aromatic, heterocyclic ring that isoptionally further substituted with one or more instances of J^(B).Specifically, ring C is 4-8 membered. Specifically, ring C is 4-7 or 5-7membered. Specific examples of Ring C include:

wherein each of rings C1-C5 is optionally and independently substituted.

Ring D is a 4-10 membered, non-aromatic, heterocyclic ring that isoptionally substituted with one or more substituents instances ofJ^(D1). Specifically, ring D is 4-8 membered. Specifically, ring D is4-7 or 5-7 membered. Specific examples of ring D include:

wherein each of rings D1-D7 is optionally substituted.

Specifically, each of Rings A-D is independently and optionallysubstituted 4-8 or 4-7 membered ring.

Each Q¹ is independently a bond, —O—, —S—, —NR′—, C(O)—, C(═NR)—,C(═NR)NR—, —NRC(═NR)NR—, CO₂-, —OC(O)—, C(O)NR′—, C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —S(O)—,—SO₂-, —SO₂NR′—, —NRSO₂-, or —NRSO₂NR′—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q¹ isindependently a bond, —O—, —S—, —NR′—, C(O)—, C(═NR)—, CO₂-, —OC(O)—,C(O)NR′—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-,—OC(O)NR′—, —S(O)—, —SO₂-, —NRSO₂-, —SO₂NR′—, NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q¹ is independently a bond, —O—,—S—, —NR′—, C(O)—, CO₂-, —OC(O)—, C(O)NR′—, C(O)NHC(O)O—,C(O)N(CH₃)C(O)O—, —NHC(O)NHC(O)O—, —N(CH₃)C(O)NHC(O)O—, —NHC(O)—,—N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-, —N(CH₃)CO₂-,—OC(O)NR′—, —S(O)—, —SO₂-, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

Each Q² is independently a bond, —O—, —S—, —NR—, C(O)—, C(═NR)—,C(═NR)NR—, —NRC(═NR)NR—, CO₂-, —OC(O)—, C(O)NR—, C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-, —OC(O)NR—, —S(O)—,—SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, CO₂SO₂-, or —(CR⁶R⁷)_(p)——Y¹. Specifically each Q² isindependently a bond, —O—, —S—, —NR′—, C(O)—, C(═NR)—, CO₂-, —OC(O)—,C(O)NR′—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-,—OC(O)NR′—, —S(O)—, —SO₂-, —NRSO₂-, —SO₂NR′—, NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² is independently —O—, —NR′—,C(O)—, CO₂-, C(O)NR′—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—,—NRSO₂-, —SO₂NR′—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² isindependently CO₂-, C(O)NR′—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-,—OC(O)NR′—, —NRSO₂-, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² isindependently —NR′—, C(O)NR′—, —NRC(O)—, —SO₂NR′—, —NRC(O)NR′—, —NRCO₂-,—OCONR′—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² is independentlyC(O)NR′—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OCONR′—, or —(CR⁶R⁷)_(p)—Y¹—.Specifically, each Q² is independently —O—, —NR′—, C(O)—, CO₂-,C(O)NR′—, —NHC(O)—, —N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-,—N(CH₃)CO₂-, —OC(O)NR′—, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NR′—,or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² is independently CO₂-,C(O)NR′—, —NHC(O)—, —N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-,—N(CH₃)CO₂-, —OC(O)NR′—, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NH—, —SO₂N(CH₃)—, or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² is independently —NR′—,C(O)NR′—, —NHC(O)—, —N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-,—N(CH₃)CO₂-, —OCONR′—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q² isindependently C(O)NR′—, —NHC(O)—, —N(CH₃)C(O)—, —NHC(O)NR′—,—N(CH₃)C(O)NR′—, —NHCO₂-, —N(CH₃)CO₂-, —OCONR′—, or —(CR⁶R⁷)_(p)—Y¹—.

Each Q³ is independently a bond, C(O)—, C(═NR)—, C(═NR)NR—,—NRC(═NR)NR—, CO₂-, C(O)NR—, —SO₂-, —SO₂N(R)-, C(O)NRC(O)O—or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q³ is independently is a bond,C(O)—, C(═NR)—, CO₂-, C(O)NR′—, —SO₂-, —SO₂NR′—, C(O)NRC(O)O—, or—(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q³ is independently C(O)—, CO₂-,C(O)NR′—, —SO₂-, —SO₂NR′—, C(O)NRC(O)O—, or —(CR⁶R⁷)_(p)—Y¹—.Specifically, each Q³ is independently C(O)—, CO₂-, C(O)NH—,C(O)N(CH₃)—, —SO₂-, —SO₂NH—, —SO₂N(CH₃)—, C(O)NHC(O)O—,C(O)N(CH₃)C(O)O—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, each Q³ isindependently C(O)—, CO₂-, C(O)NR′—, C(O)NHC(O)O—, or —(CR⁶R⁷)_(p)—Y¹—.Specifically, each Q³ is independently C(O)—, CO₂-, C(O)NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

Optionally, Q² and Q³, together with R⁵, each and independently can forma 5-7 membered, non-aromatic ring optionally substituted with one ormore instances ofJ^(E1). It is understood that the non-aromatic ringformed with R⁵ and Q² can employ a portion of Q². It is also understoodthat the non-aromatic ring formed with R⁵ and Q³ can employ a portion ofQ³.

Each Y¹ is independently a bond, —O—, —S—, —NR—, C(O)—, C(═NR)—,C(═NR)NR—, —NRC(═NR)NR—, —CO₂—, —OC(O)—, —C(O)NR—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂—, —OC(O)NR—, —S(O)—,—SO₂—, —N(R)SO₂—, —SO₂N(R)—, —NRSO₂NR—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, or —CO₂SO₂—. Specifically each Y¹ is independently a bond,—O—, —S—, —NR′—, —C(O)—, —C(═NR)—, —CO₂—, —OC(O)—, C(O)NR′—, —NRC(O)—,—NRC(O)NR′—, —NRCO₂—, —OC(O)NR′—, —S(O)—, —SO₂—, —SO₂NR′—, —NRSO₂—,—NRSO₂NR′—, —NRC(O)NRC(O)O—, or C(O)NRC(O)O—. Specifically, each Y¹ isindependently a bond, —O—, —NR′—, C(O)NR′—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂—, —OC(O)NR′—, —NRC(O)NHC(O)O—, or C(O)NHC(O)O—. Specifically,each Y¹ is independently a bond, —O—, —S—, —NR′—, C(O)—, CO₂—, —OC(O)—,C(O)NR′—, —NHC(O)—, —N(CH₃)C(O) —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂—,—N(CH₃)CO₂—, —OC(O)NR′—, —S(O)—, —SO₂-, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NH—,SO₂N(CH₃)—, -NHSO₂NH—, —N(CH₃)SO₂NH—, —N(CH₃)SO₂N(CH₃)—, C(O)NHC(O)O—,C(O)N(CH₃)C(O)O—, —NHC(O)NHC(O)O—, or —N(CH₃)C(O)NHC(O)O—. Specifically,each Y¹ is independently a bond, —O—, —NR′—, C(O)NR′—, —NHC(O)—,—N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-, —N(CH₃)CO₂-,—OC(O)NR′—, C(O)NHC(O)O—, or —NHC(O)NHC(O)O—.

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, -NCO, and Q¹-R⁵; or optionally twoJ^(A) and two J^(B), respectively, together with the atom(s) to whichthey are attached, independently form a 4-8 membered ring (e.g., spiroring or fused ring) that is optionally substituted with one or moreinstances of J^(E1). Specifically each of J^(A) and J^(B) isindependently selected from the group consisting of halogen, cyano, oxo,-NCO, and Q¹-R⁵; or optionally two J^(A) and two J^(B), respectively,together with the atom(s) to which they are attached, independently forma 5-7 membered ring that is optionally substituted with one or moreinstanced of J^(E1). The 5-7-membered ring formed with J^(A) or J^(B)can be aromatic or non-aromatic. The 5-7-membered ring formed with J^(A)or J^(B) can optionally be fused to the ring to which they are attached.In some embodiments, the 5-7-membered ring can optionally be a spiroring formed by two geminal J^(A) and two geminal J^(B), respectively.

J^(C) is independently selected from the group consisting of halogen,cyano, oxo, —OR⁵, —SR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵, C(O)NR′R⁵,C(O)NRC(O)OR⁵, —NRC(O)NRC(O)OR⁵, —NRC(O)R⁵, —NRC(O)NR′R⁵, —NRCO₂R⁵,—OC(O)NR′R⁵, —S(O)R⁵, —SO₂R⁵, —SO₂NR′R⁵, —NRSO₂R⁵, NRSO₂NR′R⁵, and—P(O)(OR^(a))₂-. Specifically, J^(C) is independently selected from thegroup consisting of —OR⁵, —SR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵,C(O)NR′R⁵, C(O)NRC(O)0R⁵, —NRC(O)NRC(O)OR⁵, —NRC(O)R⁵, —NRC(O)NR′R⁵,—NRCO₂R⁵, —OC(O)NR′R⁵, —S(O)R⁵, SO₂R⁵, —SO₂NR′R⁵, NRSO₂R⁵, and—NRSO₂NR′R⁵. Specifically, J^(C) is selected from the group consistingof halogen, cyano, oxo, —OR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵,C(O)NR′R⁵, C(O)NRC(O)OR⁵, —NRC(O)R⁵, —NRC(O)NR′R⁵, —NRCO₂R⁵, and—OC(O)NR′R⁵. Specifically, J^(C) is selected from the group consistingof halogen, cyano, oxo, —OR⁵, —NR′R⁵, C(O)R⁵, CO₂R⁵, —OC(O)R⁵,C(O)NR′R⁵, and —NRC(O)R⁵. Specifically, J^(C) is selected from the groupconsisting of halogen, cyano, oxo, —OR⁵, —NR′R⁵, C(O)NR′R⁵, and—NRC(O)R⁵. Specifically, J^(C) is selected from the group consisting of—OR⁵, —NR′R⁵, C(O)NR′R⁵, and —NRC(O)R⁵.

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, —R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), C(O)R^(b), C(═NR)R^(c), C(═NR)NR^(b)R^(c),—NRC(═NR)NR^(b)R^(c), C(O)OR^(b), —OC(O)R^(b), —NRC(O)R^(b),C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b), —OCONR^(b)R^(c),C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)), —SO₂NR^(c)R^(b),—NRSO₂R^(b), —NRSO₂NR^(c)R^(b), —P(O)(OR^(a))₂, —OP(O)(OR^(a))₂-,—P(O)₂(OR^(a)), and CO₂SO₂R^(b), or optionally, two J^(C1) and twoJ^(D1), respectively, together with the atom(s) to which they areattached, independently form a 4-8-membered ring that is optionallysubstituted with one or more instances of J^(E1). Specifically, each ofJ^(C1) and J^(D1) is independently selected from the group consisting ofhalogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a), —SO₂R^(a),—NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b), —NRC(O)R^(b),C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b), —OCONR^(b)R^(c),C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)), —SO₂NR^(c)R^(b),—NRSO₂R^(b), and —NRSO₂NR^(c)R^(b).

Optionally, two J^(C1) and two J^(D1), respectively, together with theatoms to which they are attached, independently form a 5-7-membered ringthat is optionally substituted with one or more instances of J^(E1), andfused to the respective ring to which they are attached. It isunderstood that selections of values of each J^(C1) and J^(D1) are thosethat result in the formation of stable or chemically feasible compounds.For example, suitable values of each J^(C1) and J^(D1) on a carbon atomindependently include halogen, cyano, oxo, R^(a), OR^(b), SR^(b),—S(O)R^(a), SO₂R^(a), NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), OC(O)R^(b),NR^(b)C(O)R^(b) , C(O)NR^(b)RC, NRC(O)NR^(b)R^(c), NRC(O)OR^(b),OCONR^(b)R^(c), C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), and —NRSO₂NR^(c)R^(b); and suitable valuesof J^(D1) on a nitrogen atom include R^(a), —SO₂R^(a), —SO₂N(R)R^(b),C(O)R^(b), C(O)OR^(b), C(O)NR^(b)R^(c), C(O)NRCO₂R^(b), andC(O)NR(OR^(b)). Specific examples of each J^(C1) and J^(D1) on a carbonatom independently include halogen, cyano, oxo, —R^(a), —OR^(b),—SR^(b), —S(O)R^(a), —SO₂R^(a), -NHR^(c), C(O)R^(b), C(O)OR^(b),—OC(O)R^(b), —NHC(O)R^(b), C(O)NHR^(c), —NHC(O)NHRC, —NHC(O)OR^(b) and—OCONHR^(c), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), C(O)NHCO₂R^(b),C(O)N(CH₃)CO₂R^(b), —NHC(O)NHC(O)OR^(b), —N(CH₃)C(O)NHC(O)OR^(b),C(O)NH(OR^(b))—, C(O)N(CH₃)(OR^(b)), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b). Specific examples of each J^(D1)on a nitrogen atom independently include R^(a), —SO₂R^(a), C(O)R^(b),C(O)OR^(b), C(O)NHR^(c), C(O)N(CH₃)R^(c), C(O)NHCO₂R^(b),C(O)N(CH₃)CO₂R^(b), C(O)NH(OR^(b)), and C(O)N(CH₃)(OR^(b)). Morespecific examples of each J^(C1) and J^(D1) on a carbon atomindependently include halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁ C₄ alkyl), -N(C₄ C₄ alkyl)₂,C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), C₃-C₆cycloalkyl, and CO₂H, wherein each of said alkyl groups (e.g.,represented by C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁ C₄ alkyl),-N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄alkyl), and C₃-C₆ cycloalkyl) is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), —OCO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. More specific examples of eachJ^(D1) on a nitrogen atom independently include halogen, cyano, hydroxy,oxo, C₁-C₄ alkyl, C(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), and C₃-C₆cyclo(alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), —OCO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Each J^(E1) is independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, amido, C₁-C₆ alkyl,—O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl), wherein each of said alkylgroups is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, each J^(E1) is independently selected from thegroup consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, —O(C₁-C₆alkyl), C(O)(C₁-C₆-alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl),C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), and CO₂H, wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. It isunderstood that selections of suitable J^(E1) are those that result inthe formation of stable or chemically feasible compounds. For example,suitable substituents on a carbon atom independently include halogen,cyano, hydroxy, oxo, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), C(O)(C₁-C₆—alkyl),-NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C(O)NH₂, C(O)NH(C₁-C₆ alkyl),C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl), C(O)O(C₁-C₆ alkyl),—OC(O)(C₁-C₆—NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), andCO₂H, wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. For example, suitable substituentson a nitrogen atom independently include C₁-C₆ alkyl, C(O)NH(C₁-C₆alkyl), C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆—alkyl), and C(O)O(C₁-C₆ alkyl),wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

R and R′ are each independently —H or C₁-C₆ alkyl optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy. Specifically,R and R′ are each independently —H or C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), CO₂H, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₁-C₆ alkoxyalkoxy. Specifically, R and R′ are each independently —Hor C₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, and —O(C₁-C₆alkyl). Specifically, R and R′ are each independently —H or C₁-C₆ alkyl(e.g., CH₃ or CH₂CH₃).

Optionally R′, together with R⁵ and the nitrogen atom to which they areattached, forms a 5-7 membered, non-aromatic, heterocyclic ringoptionally substituted with one or more instances of J^(D1).Specifically, the non-aromatic heterocycle is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,-NH₂, NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), C(O)NH₂,C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and CO₂R^(b); wherein each of said alkyl and alkenyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), C(O)(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, the non-aromatic heterocycle is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), C(O)(C₁-C₄alkyl), CO₂H, and CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Each R^(*) is independently: i) —H; ii) a C₁-C₆ alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₃-C₈ non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle,phenyl, 5-6 membered heteroaryl, —O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl);wherein each of said alkyl groups (e.g., represented by —O(C₁-C₆ alkyl),and C(O)(C₁-C₆-alkyl)) is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; and wherein each of said C₃-C₈ non-aromaticcarbocycle, 5-6 membered non-aromatic heterocycle, phenyl, and 5-6membered heteroaryl is independently and optionally substituted with oneor more instances of J^(E1); or iii) a C₃-C₈ non-aromatic carbocycle, ora 4-8 membered non-aromatic heterocycle, each of which is independentlyand optionally substituted with one or more instances of J^(E1).Specifically, each R* independently is: i) —H; ii) C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,amino, carboxy, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ aminoalkoxy, C₁-C₄cyanoalkoxy, C₁-C₄ hydroxyalkoxy, and C₂-C₄ alkoxyalkoxy; or iii) a 3-7membered carbocyclic ring optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₂-C₄ alkoxyalkyl, C₁-C₄ aminoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ aminoalkoxy, C₁-C₄cyanoalkoxy, C₁-C₄ hydroxyalkoxy, and C₂-C₄ alkoxyalkoxy. Specifically,each R* is i) ——H, ii) C₁-C₆ alkyl optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), C₁-C₄ alkoxy, and C₁-C₆ alkyl, wherein each alkyl optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Each R^(a) is independently: i) a C₁-C₆ aliphatic group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,amido, —O(C₁-C₆ alkyl), C(O)(C₁-C₆-alkyl), C₃-C₈ non-aromaticcarbocycle, 4-8 membered non-aromatic heterocycle, 5-10 memberedheteroaryl group, and 6-10 membered carbocyclic aryl group; wherein eachof said alkyl groups for the substituents of the C₁-C₆ aliphatic grouprepresented by Ra is optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl andcarbocyclic aryl groups for the substituents of the C₁-C₆ aliphaticgroup represented by R^(a) is optionally and independently substitutedwith one or more instances of J^(E1); ii) a C₃-C₈ non-aromaticcarbocycle, or a 4-8 membered non-aromatic heterocycle, each of which isoptionally and independently substituted with one or more instances ofJ^(E1); iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclicaryl group, each of which is optionally and independently substitutedwith one or more instances of J^(E1). Alternatively, each Ra isindependently: i) a C₁-C₆ aliphatic group optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, C(O)O(C₁-C₆-alkyl), —OC(O)(C₁-C₆-alkyl), CO₂H,C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —O(C₁-C₆ alkyl), C(O)(C₁-C₆-alkyl),C₃-C₈ non-aromatic carbocycle, 6-10 membered carbocyclic aryl, 4-8membered non-aromatic heterocycle, and 5-10 membered heteroaryl; whereineach of said alkyl groups for the substituents of the C₁-C₆ aliphaticgroup represented by R^(a) is optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; and wherein each of said carbocycle, phenyl,non-aromatic heterocycle, and heteroaryl groups for the substituents ofthe C₁-C₆ aliphatic group represented by R^(a) is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₆ alkyl, -NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,C(O)O(C₁-C₆-alkyl), OC(O)(C₁-C₆-alkyl), CO₂H, —C(O)NH₂, C(O)NH(C₁-C₆alkyl), C(O)N(C₁-C₆ alkyl)₂, —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl), eachsaid alkyl groups being optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; ii) a C₃-C₈ non-aromatic carbocyclic group, ora 4-8 membered, non-aromatic heterocyclic group, each of which isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,C(O)O(C₁-C₆-alkyl), CO₂H, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆alkyl)₂, NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —O(C₁-C₆alkyl), and C(O)(C₁-C₆-alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; oriii) a 5-10 membered heteroaryl group or a 6-10 membered carbocyclicaryl group, each of which is optionally and independently substitutedwith one or more instances of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl,NH₂, NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C(O)O(C₁-C₆-alkyl),—OC(O)(C₁-C₆-alkyl), CO₂H, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl),—O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl), wherein each of said alkylgroups is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, R^(a) is independently: i) a C₁-C₆ aliphatic groupoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen; cyano; hydroxy; oxo;-NH₂; -NH(C₁-C₆ alkyl); -N(C₁-C₆ alkyl)₂; C(O)O(C₁-C₆-alkyl);—OC(O)(C₁-C₆-alkyl); CO₂H; —O(C₁-C₆ alkyl); C(O)(C₁-C₆-alkyl); and aC₃-C₇ non-aromatic carbocyclic group, phenyl group, 4-7 memberednon-aromatic heterocyclic group, or 5-6 membered heteroaryl group, eachof which is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, C(O)O(C₁-C₆—alkyl), OC(O)(C₁-C₆-alkyl), CO₂—H,—O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl); ii) a C₃-C₇ non-aromaticcarbocyclic group optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,C(O)O(C₁-C₆-alkyl), —OC(O)(C₁-C₆-alkyl), CO₂H, —O(C₁-C₆ alkyl), andC(O)(C₁-C₆-alkyl); iii) a 4-7 membered, non-aromatic heterocyclic groupoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₆ alkyl, -NH₂, —NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,C(O)O(C₁-C₆-alkyl), —OC(O)(C₁-C₆-alkyl), CO₂H, —O(C₁-C₆ alkyl), andC(O)(C₁-C₆-alkyl); iv) a 5-6 membered heteroaryl group or a phenylgroup, each of which is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆alkyl), N(C₁-C₆ alkyl)₂, C(O)O(C₁-C₆-alkyl), —OC(O)(C₁-C₆-alkyl), CO₂H,—O(C₁-C₆ alkyl), and C(O)(C₁-C₆-alkyl). Each of the alkyl groupsreferred to in the values of R^(a), including substituents thereof,independently and optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, the optionally substituted C₁-C₆ aliphatic grouprepresented by R^(a) is an optionally substituted C₁-C₆ alkyl group.

R^(b) and R^(c) are each independently R^(a) or —H; or optionally, R^(b)and R^(c), together with the nitrogen atom(s) to which they are attached(e.g., represented by —NR^(b)R^(c), C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c),or —OCONR^(b)R^(c)), each independently form a non-aromatic, 5-7membered, heterocyclic ring that is optionally substituted with one ormore instances of J^(E1). Suitable specific substituents for theheterocyclic ring formed with R^(b) and R^(c) independently includehalogen, cyano, hydroxy, oxo, amino, carboxy, amido, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆-alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, C₂-C₆ alkoxyalkoxy, andC(O)(C₁-C₆-alkyl). Specific suitable substituents for the heterocyclicring formed with R^(b) and R^(c) independently include halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, C₁-C₄ hydroxyalkoxy, C₂-C₄ alkoxyalkoxy, CO₂(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), and CO₂H.

It is understood that selections of suitable substituents for theheterocyclic ring formed with R^(b) and R^(c) are those that result inthe formation of stable or chemically feasible compounds. For example,suitable substituents on a carbon atom independently include halogen,cyano, hydroxy, oxo, —H₂, -NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ cyanoalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₁-C₆-aminoalkoxy, C₁-C₆-cyanoalkoxy, C₁-C₆-hydroxyalkoxy,C₂-C₆-alkoxyalkoxy, C(O)(C₁-C₆-alkyl), C(O)O(C₁-C₆-alkyl),—OC(O)(C₁-C₆—alkyl), CO₂H, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl). Inanother example, suitable substituents on a carbon atom independentlyinclude halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄alkyl)₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄alkoxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₂-C₄ hydroxyalkoxy, C₂-C₄alkoxyalkoxy, —CO(C₁-C₄ alkyl), CO₂(C₁-C₄ alkyl), and CO₂H. For example,suitable substituents on a nitrogen atom independently include C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ cyanoalkyl, C(O)(C₁-C₆-alkyl), C(O)O(C₁-C₆-alkyl),—OC(O)(C₁-C₆-alkyl), CO₂H, C(O)NH₂, C(O)NH(C₁-C₆ alkyl), and C(O)N(C₁-C₆alkyl)₂. In another example, suitable substituents on a nitrogen atomindependently include C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl,C₂-C₄ alkoxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₂-C₄ hydroxyalkoxy,CO(C₁-C₄ alkyl), CO₂(C₁-C₄ alkyl), and CO₂H.

Each R^(d) is independently ——H, C₁-C₆ alkyl or C(O)(C₁-C₆ alkyl),wherein each of said alkyl moiety is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, each R^(d) isindependently ——H, or C₁-C₆ alkyl optionally substituted with one ormore groups selected from halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

p is independently 1, 2, 3 or 4. Specifically, p is independently 1 or2.

k, n and m are each independently 0, 1 or 2. Alternatively, when rings Aand B are 3-6-membered, n and m are each independently 0 or 1; and k isindependently 0, 1 or 2; and when rings A and B are 7-8-membered, n andm, are each independently 0, 1 or 2; and k is independently 0, 1 or 2.

x and y are each independently 0, 1 or 2.

z is 1 or 2.

A second set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R³ is ——H, Cl, —F, —Br, CN, CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂, -NH(C₁-C₄alkyl), or -N(C₁-C₄ alkyl)₂.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

A third set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R⁴ is i) an optionally substituted C₃-C₁₀ carbocyclic ring; ii) a C₁-C₆aliphatic group (e.g., C₁-C₆ alkyl or C₂-C₆ alkenyl group) that issubstituted with one or more substituents independently selected fromthe group consisting of J^(C), an optionally substituted, C₃-C₈non-aromatic carbocycle, and an optionally substituted, 4-10 memberednon-aromatic heterocycle; or iii) an optionally substituted, 4-10membered non-aromatic heterocycle. Values of the remaining variables ofStructural Formulae (I) and (IA), including specific values, andprovisos are each and independently as described above for the first setof variables of Structural Formulae (I) and (IA).

A fourth set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R³ is ——H, Cl, —F, —Br, CN, CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂, -NH(C₁-C₄alkyl), or -N(C₁-C₄ alkyl)₂.

R⁴ is selected from formulae A-D depicted above.

The remaining variables of Structural Formulae (I) and (IA), includingspecific values, are each and independently as described above for thefirst set of variables of Structural Formulae (I) and (IA).

A fifth set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R³ is ——H, —F, Cl, CF₃, -NH₂, -NHMe or -NMe₂.

R⁴ is i) an optionally substituted C₃-C₁₀ carbocyclic ring; ii) a C₁-C₆aliphatic group (e.g., C₁-C₆ alkyl or C₂-C₆ alkenyl group) that issubstituted with one or more substituents independently selected fromthe group consisting of J^(C), an optionally substituted, C₃-C₈non-aromatic carbocycle, and an optionally substituted, 4-10 memberednon-aromatic heterocycle; or iii) an optionally substituted, 4-10membered non-aromatic heterocycle. Values of the remaining variables ofStructural Formulae (I) and (IA), including specific values, andprovisos are each and independently as described above for the first setof variables of Structural Formulae (I) and (IA).

A sixth set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R³ is ——H, —F, Cl, CF₃, -NH₂, -NH(CH₃), or —N(CH₃)₂.

R⁴ is selected from formulae A-D depicted above.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, are each and independently as each    and independently as described above for the first set of variables    of Structural Formulae (I) and (IA).

A seventh set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H or CH₃.

R³ is ——H, —F, or Cl.

R⁴ is i) an optionally substituted C₃-C₁₀ carbocyclic ring; ii) a C₁-C₆aliphatic group (e.g., C₁-C₆ alkyl or C₂-C₆ alkenyl group) that issubstituted with one or more substituents independently selected fromthe group consisting of J^(C), an optionally substituted, C₃-C₈non-aromatic carbocycle, and an optionally substituted, 4-10 memberednon-aromatic heterocycle; or iii) an optionally substituted, 4-10membered non-aromatic heterocycle. Values of the remaining variables ofStructural Formulae (I) and (IA), including specific values, andprovisos are each and independently as each and independently asdescribed above for the first set of variables of Structural Formulae(I) and (IA).

An eighth set of variables of Structural Formula I is as follows:

R² is —H or CH₃.

R³ is ——H, —F, or Cl.

R⁴ is selected from formulae A-D depicted above.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as each and independently as described above for the    first set of variables of Structural Formulae (I) and (IA).

A ninth set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H.

R³ is —H or Cl.

R⁴ is i) an optionally substituted C₃-C₁₀ carbocyclic ring; ii) a C₁-C₆aliphatic group (e.g., C₁-C₆ alkyl or C₂-C₆ alkenyl group) that issubstituted with one or more substituents independently selected fromthe group consisting of J^(C), an optionally substituted, C₃-C₈non-aromatic carbocycle, and an optionally substituted, 4-10 memberednon-aromatic heterocycle; or iii) an optionally substituted, 4-10membered non-aromatic heterocycle. Values of the remaining variables ofStructural Formulae (I) and (IA), including specific values, andprovisos are each and independently as each and independently asdescribed above for the first set of variables of Structural Formulae(I) and (IA).

A tenth set of variables of Structural Formulae (I) and (IA) is asfollows:

R² is —H.

R³ is —H or

R⁴ is selected from formulae A-D depicted above.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as each and independently as described above for the    first set of variables of Structural Formulae (I) and (IA).

An eleventh set of variables of Structural Formulae (I) and (IA) is asfollows:

Each of R², R³ and R⁴ is independently as described in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenthset of variables of Structural Formulae (I) and (IA).

Z¹ is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —F, Cl, CN, CO₂H, CO₂(C₁-C₆alkyl), CONH₂, CONH(C₁-C₆ alkyl), or CON(C₁-C₆ alkyl)₂; and Z² is ——H,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆alkyl)₂; wherein each of said alkyl groups (e.g., represented by C₁-C₆alkyl, —O(C₁-C₆ alkyl), —CO₂(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂) is optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

A twelfth set of variables of Structural Formulae (I) and (IA) is asfollows:

Each of R², R³ and R⁴ is independently as described in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenthset of variables of Structural Formulae (I) and (IA).

Z¹ is ——H, —F, Cl, C₁-C₄ haloalkyl (e.g, CF₃), C₁-C₄ alkyl, —O(C₁-C₄alkyl), or CN.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂; wherein each of said alkyl groups (e.g., representedby C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)₂)is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

A thirteenth set of variables of Structural Formulae (I) and (IA) is asfollows:

Each of R², R³ and R⁴ is independently as described in the first set,second set, third set, fourth set, fifth set, sixth set, seventh set,eighth set, ninth set, or tenth set, of variables of Structural Formulae(I) and (IA).

Z¹ is ——H, —F, Cl, C₁-C₄ haloalkyl (e.g, CF₃), C₁-C₄ alkyl, —O(C₁-C₄alkyl), or CN.

Z² is —H or a C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

A fourteenth set of variables of Structural Formulae (I) and (IA) is asfollows:

Each of R², R³ and R⁴ is independently as described in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenthset of variables of Structural Formulae (I) and (IA).

Z¹ is ——H, —F, Cl, CF₃, CH₃, or CN.

Z² is —H or a C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae (I) and    (IA), including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

In a fifteenth set of variables of Structural Formulae (I) and (IA),values of the the variables, except R*, R and R′, of Structural Formulae(I) and (IA), including specific values, and provisos are each andindependently as described above in the first, second, third, fourth,fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth,thirteenth, or fourteenth set of variables of Structural Formulae (I)and (IA); and, where applicable:

each R* independently is: i) —H; ii) C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; or iii) a 3-7 membered carbocyclic ringoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, and C₁-C₆ alkyl, whereineach alkyl is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and

R and R′ are each independently —H or C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, and —O(C₁-C₆ alkyl); or optionally R′, together withR⁵ and the nitrogen atom to which they are attached, forms a 5-7membered, non-aromatic, heterocyclic ring optionally substituted withone or more instances of J^(D1).

A sixteenth set of variables of Structural Formulae (I) and (IA) is asfollows:

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, and Q¹-R⁵; or optionally two J^(A)and two J^(B), respectively, together with the atom(s) to which they areattached, independently form a 5-7 membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to the ringto which they are attached.

Q¹ is independently a bond, —O—, —S—, —R′—, C(O)—, CO₂-, —OC(O)—,—C(O)NR′—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂-, —OC(O)NR′—, —S(O)—, —SO₂-, —SO₂NR′—, —NRSO₂-, or —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b),—NRC(O)R^(b), C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b),—OCONR^(b)R^(c), C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), and —NRSO₂NR^(c)R^(b), or optionally, twoJ^(C1) and two J^(D1), respectively, together with the atoms to whichthey are attached, independently form a 5-7-membered ring that isoptionally substituted with one or more instances of J^(E1), and fusedto the respective ring to which they are attached. Values of theremaining variables of Structural Formulae (I) and (IA), includingspecific values, and provisos are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth setof variables of Structural Formulae (I) and (IA).

A seventeenth set of variables of Structural Formulae (I) and (IA) is asfollows:

R¹ is —H.

R² is ——H, CH₃, CH₂O—H, or -NH₂. Alternatively R² is —H or CH₂OH.

R³ is ——H, —F, Cl, C₁-4 alkyl, or C₁-4 haloalkyl. Alternatively, R³ is——H, —F, or Cl.

Z¹ is ——H, —F, or Cl.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Z³ is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

The remaining variables are as decribed above in any set of variablesfor Structural Formulae (IA) and (I) as applicable.

An eighteenth set of variables of Structural Formulae (I) and (IA) is asfollows:

R¹ is —H.

R² is —H or —CH₂OH.

R³ is ——H, —F, or Cl. Alternatively R³ is —F or Cl.

Z¹ is ——H, —F, or Cl.

Z² and Z³ are —H.

The remaining variables are each and independently as decribed above inany set of variables for Structural Formulae (IA) and (I).

A nineteenth set of variables of Structural Formulae (I) and (IA) is asfollows:

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; iv) an optionallysubstituted, 4-7 membered non-aromatic heterocycle; v))an optionallysubstituted phenyl group; vi) an optionally substituted 5-6 memberedheteroaryl ring; or optionally, together with R and the nitrogen atom towhich it is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ CO₂H, CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy,—NRCO(C₁-C₄ alkyl), CONR(C₁-C₄ alkyl), —NRCO₂(C₁-C₄ alkyl), a C₃-C₇non-aromatic carbocycle optionally substituted with one or moreinstances of J^(E1), a 4-7 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1); and a phenyloptionally substituted with one or more instances of J^(E1); and

wherein each of said carbocycle, heterocycle, phenyl and heteroaryrepresented by R⁵ is independently and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), C(O)O(C₁-C₄ alkyl) and CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

R¹, R², R³, Z¹, Z², and Z³ are each independently as described in theseventeenth or eighteenth set of variables above.

The remaining variables are each and independently as decribed above inany set of variables for Structural Formulae (IA) and (I).

In some embodiments, the variables of Structural Formulae (IA) and (I)are each and independently as described above in any set of variables,provided that: R⁴ is:

n and m are each independently 0 or 1 when rings A and B are3-6-membered; or n and m are each independently 0, 1 or 2 when rings Aand B are 7-10-membered; and

provided that if Y¹ is a bond, then R⁵ is neither —H nor a C₁-C₆aliphatic group; and

provided that if each Q² and Q³ independently is a bond, then R⁵ isneither —H nor a C₁-C₆ aliphatic group.

In another embodiment, the present invention is directed to the use ofcompounds represented by any one of the Structural Formulae II, III, IV,and V, depicted below, or pharmaceutically acceptable salts thereof, forany of the uses described above:

The first set of variables of Structural Formulae II-V is as follows:

Z¹ is ——H, —F, Cl, C₁-C₄ haloalkyl (e.g, CF₃), C₁-C₄ alkyl, —O(C₁-C₄alkyl), or CN.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

R³ is ——H, Cl, —F, —Br, CN, CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂, -NH(C₁-C₄alkyl), or -N(C₁-C₄ alkyl)₂. Specifically, R³ is ——H, —, Cl, CF₃, -NH₂,-NH(CH₃), or —N(CH₃)₂. Specifically, R³ is ——H, Cl, or —F. Specifically,R³ is Cl.

Each R and R′ are independently —H or C₁-C ₆alkyl.

-   Definitions of rings A-D of formulae II-V, including specific    variables, are each and independently as described above for the    first set of variables of Structural Formulae (I) and (IA), wherein    each of rings A-D is independently an optionally substituted, 4-7    membered ring. Values of the remaining variables of Structural    Formulae II-V, including specific values, and provisos are each and    independently as described above for the first set of variables of    Structural Formulae (I) and (IA).

A second set of variables of Structural Formulae II, III, IV and V is asfollows:

Z¹ is ——H, —F, Cl, CF₃, CH₃, or CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae II-V,    including specific values, and provisos are each and independently    as described above for the first set of variables of Structural    Formulae II-V.

A third set of variables of Structural Formulae II, III, IV and V is asfollows:

Z¹ is ——H, —F or CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

-   Values of the remaining variables of Structural Formulae II-V,    including specific values, and provisos are each and independently    as described above for the first set of variables of Structural    Formulae II-V.

A fourth set of variables of Structural Formulae II, III, IV and V is asfollows:

Z¹ is ——H, —F or CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

R³ is ——H, —Cl or —F.

-   Values of the remaining variables of Structural Formulae II-V,    including specific values, and provisos are each and independently    as described above for the first set of variables of Structural    Formulae II-V.

A fifth set of variables of Structural Formulae II, III, IV and V is asfollows:

Z¹ is ——H, —F or CN.

Z² is H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

R³ is —H, Cl, F, CF3,NH₂,NH(CH₃), or N(CH₃)2.

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl),-NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or CH₃.

R¹¹ and R¹² are each independently —H or CH₃.

R¹³ and R¹⁴ are each independently —H or CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

-   Values of the remaining variables of Structural Formulae II-V,    including specific values, and provisos are each and independently    as described above for the first set of variables of Structural    Formulae II-V.

A sixth set of variables of Structural Formulae II, III, IV and V is asfollows:

Z¹ is ——H, —F or CN.

Z² is —H or an optionally substituted C₁-C₆ alkyl.

R³ is ——H, —Cl or —F.

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl),NH₂, -NH(C₁-C₄ alkyl) or -N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or CH₃.

R¹¹ and R¹² are each independently —H or CH₃.

R¹³ and R¹⁴ are each independently —H or CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

-   Values of the remaining variables of Structural Formulae II-V,    including specific values, and provisos are each and independently    as described above for the first set of variables of Structural    Formulae II-V.

In a seventh set of variables of Structural Formulae II-V, values forvariables, except R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, and R¹⁴, of StructuralFormulae II-V, including specific values, are each and independently asdescribed above for the first, second, third, or fourth set of variablesof Structural Formulae II-V; and

R⁶ and R⁷ are each independently —H or C₁-C₄ alkyl, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl),NH₂, -NH(C₁-C₄ alkyl) or —N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or C₁-C₄ alkyl.

R¹¹ and R¹² are each independently —H or C₁-C₄ alkyl.

R¹³ and R¹⁴ are each independently —H or C₁-C₄ alkyl, or together withthe carbon atoms to which they are attached they form a cyclopropanering.

In an eighth set of variables of Structural Formulae II-V, values forvariables of Structural Formulae II-V, including specific values, areeach and independently as described above for the first set of variablesof Structural Formulae II-V.

It is provided that when Q²-R⁵ is —OR⁵ or —NR′R⁵, ring A is furthersubstituted with one or more instances of J^(A) other than —H.

It is provided that if Q³ is C(O)—, then R⁵ is a substituted C₁-C₆aliphatic group (e.g., C₁-C₆ alkyl group or C₂-C₆ alkenyl group); anoptionally substituted C₃-C₈ non-aromatic carbocycle; an optionallysubstituted, 6-10-membered carbocyclic aryl group; an optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted, 5-10 membered heteroaryl group. In one embodiment, theC₁-C₆ aliphatic group is substituted with one or more instances ofJ^(C1), wherein J^(C1) is independently selected from: an optionallysubstituted, C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; an optionally substituted, 5-10membered heteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); SO₂R^(a);—NR^(b)R^(c); C(O)R^(b); C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b);C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c);C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b); C(O)NR(OR^(b)); —SO₂NR^(c)R^(b);—NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); or optionally two J^(C1) and twoJ^(D1), respectively, together with the atoms to which they areattached, independently form a 5-7-membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to therespective ring to which they are attached.

In a ninth set of variables of Structural Formulae II-V, values forvariables of Structural Formulae II-V, including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

A tenth set of variables of Structural Formulae II-V is as follows:

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, and Q¹-R⁵; or optionally two J^(A)and two J^(B), respectively, together with the atom(s) to which they areattached, independently form a 5-7 membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to the ringto which they are attached.

Q¹ is independently a bond, —O—, —S—, —NR—, C(O)—, CO₂-, —OC(O)—,C(O)NR—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, or—(CR⁶R⁷)_(p)—Y¹—.

Q² is independently a bond, —O—, —S—, —NR—, C(O)—, CO₂-, —OC(O)—,C(O)NR—, C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, or—(CR⁶R⁷)_(p)—Y¹—.

Q³ is independently a bond, C(O)—, CO₂-, C(O)NR—, —SO₂-, —SO₂N(R)-,C(O)NRC(O)O—or —(CR⁶R⁷)_(p)—Y¹—.

R⁵ is: i) —H; ii) a C₁-C₆ aliphatic group optionally substituted withone or more instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycle,or 6-10 membered carbocyclic aryl group, each optionally andindependently substituted with one or more instances of J^(C1); or iv) a4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroarylgroup, each optionally and independently substituted with one or moreinstances of J^(D1).

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b),—NRC(O)R^(b), C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b),—OCONR^(b)R^(c), C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), and —NRSO₂NWR^(b), or optionally, twoJ^(C1) and two J^(D1), respectively, together with the atoms to whichthey are attached, independently form a 5-7-membered ring that isoptionally substituted with one or more instances of J^(E1), and fusedto the respective ring to which they are attached.

Ring A is a C₃-C₈ non-aromatic carbocycle optionally and independentlyfurther substituted with one or more instances of J^(A).

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh,eighth, or ninth set of variables of Structural Formulae II-V.

In another embodiment, the present invention is directed to the use ofcompounds represented by the Structural Formula below XI(A) or XI(B), ora pharmaceutically acceptable salt thereof, for any of the usesdescribed above.

A first set of variables of Structural formulae XI(A) and XI(B) is asfollows:

Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl,C₂-C₆ alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆alkyl), C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂,—C(O)(C₁-C₆-alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), and CO₂R^(b); wherein each of said alkyl andalkenyl groups is optionally and independently substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, ring A is a 5-7 membered, non-aromatic carbocyclicring optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C 4 alkyl),-N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄ alkyl), CO₂H, andCO₂(C₁-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, ring Ais a 5-7 membered carbocyclic ring optionally further substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₂ alkyl),-NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl,C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy,C₂-C₄ alkoxyalkoxy, CO₂H, and CO₂ (C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl),-NH₂, -NH(C₁-C₄ alkyl), or -N(C₁- C₄ alkyl)₂.

Each R⁹ is independently —H or CH₃.

R¹¹ and R¹² are each independently —H or CH₃.

R¹³ and R¹⁴ are each independently —H or CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R and R′ are independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A second set of variables for Structural formulae XI(A) and XI(B) is asfollows:

Values of Ring A, R, R′, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³ and R¹⁴,including specific values, are each and independently as described abovein the first set of variables of Structural formulae XI(A) and XI(B).

Variable x is 0 or 1 and variable n is 0 or 1.

Values of the remaining other variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A third set of variables for Structural formulae XI(A) and XI(B) is asfollows:

Values of Ring A, R, R′, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the second set of variables of Structural formulae XI(A) and XI(B).

Q² is —O—, —NR′—, CO—, C(O)NR′—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OCONR′—, —NRSO₂-, —SO₂NR′—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, Q² is—O—, -NH—, —N(CH₃)—, C(O)—, CO₂—, C(O)NH—, C(O)N(CH₃)—, —NHC(O)—,—N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-, —N(CH₃)CO₂-,—OC(O)NR′—, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NH—, —SO₂N(CH₃)—, or—(CR⁶R⁷)_(p)—Y¹—.

Values of the remaining variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A fourth set of variables for Structural formulae XI(A) and XI(B) is asfollows:

Values of Ring A, Q², R, R′, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the third set of variables of Structural formulae XI(A) and XI(B).

R⁵ is independently i) —H; ii) a C₁-C₆-aliphatic group (e.g.,C₁-C₆-alkyl or C₂-C₆-alkenyl group) optionally substituted with one ormore instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycleoptionally substituted with one or more instances of J^(C1); iv) aphenyl group optionally substituted with one or more instances ofJ^(C1); v) a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1) or vi) a 5-6 memberedheteroaryl ring optionally substituted with one or more instances ofJ^(D1).

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a)—,—SO₂R^(a), -NHR^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), C(O)NHCO₂R^(b),C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b). Values of the remaining variablesof Structural formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

A fifth set of variables for structure Structural formulae XI(A) andXI(B) is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the fourth set of variables of Structural formulae XI(A) and XI(B).

Ring A is optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), CO₂H, and CO₂(C₁-C₄ alkyl), whereineach of said alkyl groups is optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A sixth set of variables for Structural formulae XI(A) and XI(B) is asfollows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the fifth set of variables of Structural formulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below:

wherein each of rings A1-A27 is independently and optionally furthersubstituted with one or more substituents. Suitable substituents are asdescribed above for ring A in the first set of variables of Structuralformulae XI(A) and XI(B). Values of the remaining variables ofStructural formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

A seventh set of variables of Structural formulae XI(A) and XI(B) is asfollows:

Values of the group —[CR¹³R¹⁴]_(x)-ringA-Q²-R⁵, Q², R, R′, R⁶, R⁷, R⁸,R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n, including specific values, are each andindependently as described above in the sixth set of variables ofStructural formulae XI(A) and XI(B).

Each R⁵ is independently: i) —H; ii) a C₁-C₆-aliphatic group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), CO₂H, C₃-C₈non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle,and 5-6 membered heteroaryl; or iii) a C₃-C₇ non-aromatic carbocycle, a4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 memberedheteroaryl ring, each of which is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), and CO₂H; wherein eachof said alkyl groups for the substituents of the aliphatic group,carbocycle, heterocycle, phenyl and heteroaryl group represented by R⁵is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, andheteroaryl for the substituents of the C₁-C₆-aliphatic group representedby R⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy. Values of the remaining variables ofStructural formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

An eighth set of variables of Structural formulae XI(A) and XI(B) is asfollows:

Values of Q², R, R′,R⁵, R⁶, R⁷, R⁸,R⁹, R¹¹, R¹², R¹³ , R¹⁴, x and n,including specific values, are each and independently as described abovein the seventh set of variables of Structural formulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below

wherein each of rings A6, A8, A11, A14 and A15 is optionally andindependently further substituted.

R⁸ independently is halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂. Values of the remaining variablesof Structural formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

A ninth set of variables of Structural formulae XI(A) and XI(B) is asfollows:

Values of the group —[CR¹³R¹⁴]_(x)-ringA-Q²-R⁵, Q², R, R′, R⁶, R⁷, R⁸,R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n, including specific values, are each andindependently as described above in the eighth set of variables ofStructural formulae XI(A) and XI(B).

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; or iv) anoptionally substituted, 4-7 membered non-aromatic heterocycle. Each ofsaid alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy,optionally substituted, C₃-C₇ non-aromatic carbocycle, and optionallysubstituted, 4-7 membered non-aromatic heterocycle. Each of saidcarbocycles and heterocycles represented by R⁵, and referred to for thesubstituents of the C₁-C₆ alkyl group represented by R⁵ is independentlyand optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), and CO₂H,wherein each of said alkyl groups (e.g., represented by C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl),—OC(O)(C₁-C₄ alkyl), and C(O)O(C₁-C₄ alkyl)) is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Values of theremaining variables of Structural formulae XI(A) and XI(B), includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

A tenth set of variables of Structural formulae XI(A) and XI(B) is asfollows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the seventh set of variables of Structural formulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below:

wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 isindependently and optionally further substituted. Suitable substituentsare as described above for ring A in the first set of variables ofStructural formulae XI(A) and XI(B).

Values of the remaining variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

An eleventh set of variables of Structural formulae XI(A) and XI(B) isas follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, are each and independently as described abovein the seventh set of variables of Structural formulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below:

wherein each of rings A5-A7, A21, A24 and A26 is independently andoptionally further substituted. Suitable substituents are as describedabove for ring A in the first set of variables of Structure FormulaeXI(A) and XI(B). Values of the remaining variables of Structuralformulae XI(A) and XI(B), including specific values, and provisos areeach and independently as described above in the first set of variablesof Structural Formulae (I) and (IA).

In a twelfth set of variables of Structural formulae XI(A) and XI(B),values of the variables for Structural formulae XI(A) and XI(B),including specific values, and provisos are each and independently asdescribed above in the first set of variables of Structural Formulae (I)and (IA).

In a thirteenth set of variables of Structural Formulae XI(A) and XI(B),values of the variables for Structural Formulae XI(A) and XI(B),including specific values, are each and independently as described abovein the sixteenth set of variables of Structural Formulae (I) and (IA),or in the tenth set of variables of Structural Formulae II-V.

In another embodiment, the present invention is directed to the use ofcompounds represented by Structural Formula below XII(A) or XII(B), or apharmaceutically acceptable salt thereof, for any of the uses describedabove:

A first set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl,C₂-C₆ alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and CO₂R^(b); wherein each of said alkyl and alkenyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, Ring B is optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), CO₂H, andCO₂(C₁-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, Ring Bis optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, —NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl,C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy,C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, CO₂H, andCO₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R⁹ is —H or CH₃.

R¹¹ and R¹² are each independently —H or CH₃.

R¹³ and R¹⁴ are each independently —H or CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R and R′ are independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A second set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of Ring B, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³ and R¹⁴, includingspecific values, are each and independently as described above in thefirst set of variables of Structural Formulae XII(A) and XII(B).

Variable y=0 or 1.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A third set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of Ring B, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³ and R¹⁴ and y,including specific values, are each and independently as described abovein the second set of variables of Structural Formulae XII(A) and XII(B).

Q³ is independently C(O)—, CO₂-, C(O)NH—, C(O)N(CH₃)—, C(O)NHC(O)O—,C(O)N(CH₃)C(O)O—, —SO₂-, —SO₂NH—, —SO₂N(CH₃)—, or (CR⁶R⁷)_(p)—Y¹—.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A fourth set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of Ring B, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³ and R¹⁴ and y,including specific values, are each and independently as described abovein the third set of variables of Structural Formulae XII(A) and XII(B).

R⁵ is independently i) —H; ii) C₁-C₆-aliphatic group (e.g., C₁-C₆-alkylor C₂-C₆-alkenyl group) optionally substituted with one or moreinstances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycle optionallysubstituted with one or more instances of J^(C1); iv) a phenyl groupoptionally substituted with one or more instances of J^(C1); v) a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(D1) or vi) a 5-6 membered heteroaryl ringoptionally substituted with one or more instances of J^(D1).

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —SOR^(a),—SO₂R^(a), -NHR^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), C(O)N(CH₃)R^(c),—N(CH₃)C(O)NH^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), C(O)NHCO₂R^(b),C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b). Values of the remaining variablesof Structural Formulae XII(A) and XII(B), including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

A fifth set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of Ring B, Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, are each and independently as described abovein the fourth set of variables of Structural Formulae XII(A) and XII(B).

Ring B is optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), CO₂H, and CO₂(C₁-C₄ alkyl), whereineach of said alkyl groups is optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), andC₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A sixth set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, are each and independently as described abovein the fifth set of variables of Structural Formulae XII(A) and XII(B).

Ring B is independently selected from one of the structures depictedbelow:

wherein each of rings B1-B9 is optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl),CO₂H and CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, each of rings B1 to B9 is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₂alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy,C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, CO₂H, and CO₂(C₁-C₄ alkyl).

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A seventh set of variables of Structural Formulae XII(A) and XII(B) isas follows:

Values of ring B, Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, are each and independently as described abovein the sixth set of variables of Structural Formulae XII(A) and XII(B).

Each R⁵ is independently: i) —H; ii) a C₁-C₆-aliphatic group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), CO₂H, C₃-C₈non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle,and 5-6 membered heteroaryl; or iii) a C₃-C₇ non-aromatic carbocycle, a4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 memberedheteroaryl ring, each of which is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl), and CO₂H; wherein eachof said alkyl groups for the substituents of the aliphatic group,carbocycle, heterocycle, phenyl and heteroaryl group represented by R⁵is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, andheteroaryl for the substituents of the C₁-C₆-aliphatic group representedby R⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

An eighth set of variables of Structural Formulae XII(A) and XII(B) isas follows:

Values of Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³ and R¹⁴ and y,including specific values, are each and independently as described abovein the seventh set of variables of Structural Formulae XII(A) andXII(B).

The group (ring B)-Q³-R⁵ is

wherein ring B2 is optionally and independently further substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₂ alkyl),-NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl,C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy,C₂-C₄ alkoxyalkoxy, CO₂H, and CO₂(C₁-C₄ alkyl).

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

A ninth set of variables of Structural Formulae XII(A) and XII(B) is asfollows:

Values of the group (ring B)-Q³-R⁵, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹²,R¹³, R¹⁴, and y, including specific values, are each and independentlyas described above in the eighth set of variables of Structural FormulaeXII(A) and XII(B).

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; or iv) anoptionally substituted, 4-7 membered non-aromatic heterocycle, whereinsaid alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy,optionally substituted, C₃-C₇ non-aromatic carbocycle, and optionallysubstituted, 4-7 membered non-aromatic heterocycle. Each of saidcarbocycles and heterocycles represented by R⁵, and referred to for thesubstituents of the C₁-C₆ alkyl group represented by R⁵ is independentlyand optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,C(O)(C₁-C₄ OC(O)(C₁-C₄ alkyl), C(O)O(C₁-C₄ alkyl) and CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first set of variables ofStructural Formulae (I) and (IA).

In a tenth set of variables of Structural Formulae XII(A) and XII(B),values of the variables for Structural Formulae XII(A) and XII(B),including specific values, are each and independently as described abovein the first set of variables of Structural Formulae (I) and (IA).

In an eleventh set of variables of Structural Formulae XII(A) andXII(B), values of the variables for Structural Formulae XII(A) andXII(B), including specific values, are each and independently asdescribed above in the sixteenth set of variables of Structural Formulae(I) and (IA), or in the tenth set of variables of Structural FormulaeII-V.

In another embodiment, the present invention is generally directed tothe use of compounds represented by Structural Formula below XIII, or apharmaceutically acceptable salt thereof, for any of the uses describedabove.

A first set of variables of Structural Formula XIII is as follows:

Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, C₂-C₆alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ C(O)NH₂,C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and CO₂R^(b); wherein each of said alkyl and alkenyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, ring C is optionally further substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), CO₂H, and CO₂(C₁-C₄ alkyl),wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl),CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, ring C isoptionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, -NH₂, —NH(C₁-C₂ alkyl), NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, CO₂H, and CO₂(C₁-C₄alkyl).

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R⁹ is —H or CH₃.

R¹¹ and R¹² are each independently —H or CH₃.

Each R and R′ are independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

A second set of variables of Structural Formula XIII is as follows:

Values of Ring C, R, R′, R⁶, R⁷, R⁹, R¹¹ and R¹², including specificvalues, are each and independently as described above in the first setof variables of Structural Formula XIII.

R¹⁰ is —H or C₁-C₆-alkyl.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

A third set of variables of Structural Formula XIII is as follows:

Values of R, R′R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R¹², including specific values,are each and independently as described above in the first set ofvariables of Structure Formula XIII.

Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄alkyl), CO₂H and CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

A fourth set of variables of Structural Formula XIII is as follows:

Values of R, R′, R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R¹², including specificvalues, are each and independently as described above in the second setof variables of Structure Formula XIII.

Ring C is independently selected from:

wherein each of rings C₁-C5 is optionally and independently substituted.Suitable substituents are as described above for ring C in the first setof variables of Structural Formula XIV.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

In a fifth set of variables of Structural Formula XIII, values of thevariables for Structural Formula XIII, including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

In another embodiment, the present invention is generally directed tothe use of compounds represented by Structural Formula below XIV, or apharmaceutically acceptable salt thereof for any of the uses describedabove.

A first set of variables of Structural Formula XIV is as follows:

Ring D is 4-7 membered, non-aromatic, heterocyclic ring optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),C(O)NH₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and CO₂R^(b); wherein each of said alkyl and alkenyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, ring D is optionally further substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), CO₂H andCO₂(C₁-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, ring D is optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, —NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂,C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl,C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy,CO₂H, and C O₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R¹³ and R¹⁴ are each independently —H or CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each of R and R′ are independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural Formula XIV, includingspecific values, and provisos are each and independently as describedabove in the first set of variables of Structural Formulae (I) and (IA).

A second set of variables of Structural Formula XIV is as follows:

Values for Ring D, R, R′, R⁶, R⁷, R¹³ and R¹⁴, including specificvalues, are each and independently as described above in the first setof variables of Structural Formula XIV.

Value z is 1.

Values of the remaining variables of Structural Formula XIV, includingspecific values, and provisos are each and independently as describedabove for the first set of variables of Structural Formulae (I) and(IA).

A third set of variables of Structural Formula IV is as follows:

Values for z, R, R′, R⁶, R⁷, R¹³ and R¹⁴, including specific values, areeach and independently as described above in the second set of variablesof Structural Formula XIV.

Ring D is independently selected from the group consisting of

wherein each of rings D1-D7 is optionally and independently substituted.Suitable substituents are as described above for ring D in the first setof variables of Structural Formula XIV.

Each R^(d) is independently ——H, C₁-C₆ alkyl or C(O)(C₁-C₆ alkyl),wherein each of said alkyl moiety is optionally and independentlysubstituted with one or more groups selected from halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C 4 alkyl), CO(C₁-C₄ alkyl), CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, each R^(d) is independently —H or C₁-C₆ alkyloptionally and independently substituted with one or more groupsselected from halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), CO₂H,CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formula XIV, includingspecific values, and provisos are each and independently as describedabove for the first set of variables of Structural Formulae (I) and(IA).

In a fourth set of variables of Structural Formula XIV, values of thevariables for Structural Formula XIV, including specific values, andprovisos are each and independently as described above in the first setof variables of Structural Formulae (I) and (IA).

In another embodiment, the compounds of Structural Formulae I-IV andXI-XIV, and pharmaceutically acceptable salts thereof, are independentlyas described above; and provided that, where applicable, if Y¹ is abond, then R⁵ is neither ——H, nor an unsubstituted C₁-C₆ aliphaticgroup. Specifically, if Y¹ is a bond, then R⁵ is a substituted C₁-C₆aliphatic group; an optionally substituted C₃-C₈ non-aromaticcarbocycle; an optionally substituted, 6-10-membered carbocyclic arylgroup; an optionally substituted, 4-8 membered non-aromatic heterocycle;and an optionally substituted, 5-10 membered heteroary group.Specifically, the C₁-C₆ aliphatic group represented by R⁵ is substitutedwith one or more instances of J^(C1), wherein J^(C1) is independentlyselected from: an optionally substituted, C₃-C₈ non-aromatic carbocycle;an optionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; anoptionally substituted, 5-10 membered heteroaryl group; —OR^(b);—SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c); C(O)R^(b); C(O)OR^(b);—OC(O)R^(b); —NRC(O)R^(b); C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c);—NRC(O)OR^(b); —OCONR^(b)R^(c); C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b);C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); oroptionally two J^(C1) and two J^(D1), respectively, together with theatoms to which they are attached, independently form a 5-7-membered ringthat is optionally substituted with one or more instances of J^(E1), andfused to the respective ring to which they are attached.

In yet another embodiment, the compounds of Structural Formulae IA-IVand XI-XIV, and pharmaceutically acceptable salts thereof, areindependently as described above; and provided that, where applicable,if Q² is a bond, then R⁵ is neither —H nor a C₁-C₆ aliphatic group; andprovided that if Q³ is a bond, then R⁵ is neither —H nor a C₁-C₆aliphatic group. Specifically, if Q² and Q³ are each and independently abond, then R⁵ is an optionally substituted C₃-C₈ non-aromaticcarbocycle; an optionally substituted, 6-10-membered carbocyclic arylgroup; an optionally substituted, 4-8 membered non-aromatic heterocycle;or an optionally substituted, 5-10 membered heteroary group.Specifically, if Q² and Q³ are each and independently a bond, then R⁵ isan optionally substituted C₃-C₈ non-aromatic carbocycle; or anoptionally substituted, 4-8 membered non-aromatic heterocycle.

In yet another embodiment, the compounds are represented by StructuralStructural Formula (I), or pharmaceutically acceptable salts thereof,wheren each variables of the formulae are independently as describedabove; and wherein:

R⁴ is:

Ring E is a C₄-C₈ non-aromatic carbocycle optionally further substitutedwith one or more instances of J^(A).

Rings F is a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1).

Each of rings G1 and G2 is independently a 5-10 membered non-aromaticbridged carbocycle optionally substituted with one or more instances ofJ^(A).

Q² is independently bond, —O—, —S—, —NR—, C(O)—, C(═NR)—, CO₂-, —OC(O)—,—C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; or iv) anoptionally substituted, 4-7 membered non-aromatic heterocycle; oroptionally, together with R and the nitrogen atom to which it isattached, form a 5-7 membered, optionally substituted non-aromaticheterocycle. The alkyl group represented by R⁵ is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), C₁-C₄ alkoxy, an optionally substituted, C₃-C₇ non-aromaticcarbocycle, and an optionally substituted, 4-7 membered non-aromaticheterocycle; wherein each of said carbocycles and heterocyclesrepresented by R⁵, and referred to for the substituents of the C₁-C₆alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl) and CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Each of R⁸ and R⁹ is independently ——H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R¹¹, R¹², R¹³ and R¹⁴ are each independently ——H, halogen, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or optionally,R¹³ and R¹⁴, together with the carbon atom to which they are attached,form a cyclopropane ring, optionally substituted with one or moreinstances of methyl.

R²¹, R²², R²³ and R²⁴ are each independently ——H, halogen, —O—H, orC₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

Values of the remaining variables of Structural formula I, includingspecific values, and provisos are each and independently as describedabove in any one of the first through fifteenth sets of variables ofStructural Formula I.

In yet another embodiment, the compounds represented by StructuralFormula (I) or pharmaceutically acceptable salts thereof areindependently as described above in the preceding paragraph; and ring Fis selected from any one of rings F1-F6:

each of rings F1-F6 optionally and independently substituted; and eachR^(f) is independently —H or C₁-C₆ alkyl optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy and C₂-C₆ alkoxyalkoxy.

In yet another embodiment, the compounds represented by StructuralFormula (XIA) or (XIB), or pharmaceutically acceptable salts thereof areas described above; and

the group —[C(R¹³R¹⁴)]_(x)-ringA-Q²-R⁵ is independently:

wherein:

each of rings A14 and A28 is optionally and independently furthersubstituted; and

values of the remaining variables of Structural Formulae (XIA) and(XIB), including specific values, and provisos are each andindependently as described above in any one of the first througheleventh sets of variables of Structural Formulae (XIA) and (XIB).

In yet another embodiment, the compounds represented by StructuralFormula (XIA) or (XIB), or pharmaceutically acceptable salts thereof areindependently as described above in the preceding paragraph; and R⁵ isan optionally substituted C₁-C₆ alkyl group; an optionally substituted,C₃-C₇ non-aromatic carbocycle; or an optionally substituted, 4-7membered non-aromatic heterocycle; or optionally, together with R andthe nitrogen atom to which it is attached, form a 5-7 membered,optionally substituted non-aromatic heterocycle. Specifically, R⁵ is anoptionally substituted, 4-7 membered non-aromatic heterocycle; oroptionally, together with R and the nitrogen atom to which it isattached, form a 5-7 membered, optionally substituted non-aromaticheterocycle.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Ring E is a C₄-C₁₀ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A).

Rings F is a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1). Specific examples ofring F includes:

Additional example includes

Each of rings F1-F7 optionally and independently substituted. Exemplarysubstituents for ring F (including rings F1-F7) include halogen, cyano,hydroxy, C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with oneor more substituents selected from the group consisting of halogen,cyano, hydroxy, and —O(C₁-C₄ alkyl).

R^(f) is independently —H or C₁-C₆ alkyl optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy and C₂-C₆ alkoxyalkoxy.

R⁹ is independently ——H, halogen, cyano, hydroxy, amino, carboxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,or C₂-C₆ alkoxyalkoxy.

R¹¹, R¹², R¹³ and R¹⁴ are each independently ——H, halogen, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

Optionally, R¹³ and R¹⁴, together with the carbon atom to which they areattached, form a cyclopropane ring, optionally substituted with one ormore instances of methyl.

s is 0, 1 or 2.

x is 0, 1 or 2.

The remaining variables are each and independently as described above inany one of the sets of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (I) or (IA), or pharmaceutically acceptable salts thereof,wherein:

Ring E is a C₄-C₈ non-aromatic carbocycle optionally further substitutedwith one or more instances of J^(A).

R⁹ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

The other varibales are each and independently as described in thepreceeding paragraph.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Each of rings G1-G4 is independently a 5-10 membered non-aromaticbridged ring optionally further substituted with one or more instancesof J^(A).

Eing G5 is a 5-10 membered non-aromatic bridged ring optionally furthersubstituted with one or more instances of J^(B).

X is —O—, —S—, or —NR^(g)—.

R⁸ and R⁹ are each independently ——H, halogen, cyano, hydroxy, amino,carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy, or C₂-C₆ alkoxyalkoxy.

R¹³ and R¹⁴ are each independently ——H, halogen, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

Optionally, R¹³ and R¹⁴, together with the carbon atom to which they areattached, form a cyclopropane ring, optionally substituted with one ormore instances of methyl.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently ——H, halogen, —O—H,C₁-C₆alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy. Specifically, R²¹, R²², R²³, R²⁴, and R²⁵ areeach independently ——H, halogen, —O—H, C₁-C₆alkoxy, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, C₁-C₆alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),—C(O)NH₂, C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆—NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl).

R^(g) is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy.

q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

The remaining variables are each and independently as described above inany set of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), pharmaceutically acceptable salts thereof, wherein:

R⁴ is:

wherein rings G1 and G2 are each and independently a 5-10 memberednon-aromatic bridged ring optionally further substituted with one ormore instances of J^(A).

Each of R⁸ and R⁹ is independently ——H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R²¹, R²², R²³, and R²⁴ are each independently ——H, halogen, —O—H, orC₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy.

Q² is independently a bond, —O—, —S—, —NR—, —C(O)—, C(═NR)—, CO₂-,—OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—,—NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—. Alternatively Q² is independently —O—, —CO₂-, —OC(O)—,—C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-, —OC(O)NR—, —CO₂SO₂-, —P(O)₂O—,or —(CR⁶R⁷)_(p)—Y¹—. Alternatively Q² is independently —O—or CO₂-.

In some embodiments, rings E and G (including G1-G5) are optionally andindependently further substituted with one or more instances of J^(A)(for carbocycle) or J^(B) (for heterocycle), wherein each of J^(A) andJ^(B) is independently selected from the group consisting of halogen,cyano, oxo, -NCO, and Q¹-R⁵, and wherein:

Q¹ is independently a bond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂-,—OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—,—NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—; and Y¹ is independently a bond, —O—, —S—, —NR′—,—C(O)—, —C(═NR)—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —S(O)—,—SO₂-, —SO₂NR′—, —NRSO₂-, or —NRSO₂NR′—. Alternatively: Q¹ isindependently a bond, —O—, —S—, —NR—, —C(O)—, —CO₂-, —OC(O)—, —C(O)NR—,—C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂- -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—; and Y¹ is independently —O—, —CO₂-, —OC(O)—, —C(O)NR—,—NRC(O)—, —NRC(O)NR—, —NRCO₂-, or —OC(O)NR—.

In yet another embodiment, Q¹ and Y¹ are each independently as describedabove in the preceeding paragraph, and:

R⁵ is independently i) —H; ii) a C₁-C₆-aliphatic group optionallysubstituted with one or more instances of J^(C1); iii) a C₃-C₈non-aromatic carbocycle optionally substituted with one or moreinstances of J^(C1); iv) a phenyl group optionally substituted with oneor more instances of J^(C1); v) a 4-8 membered non-aromatic heterocycleoptionally substituted with one or more instances of J^(D1) or vi) a 5-6membered heteroaryl ring optionally substituted with one or moreinstances of J^(D1); and

each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), -NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),—C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b) , —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b).

In some specific embodiments, the compounds are represented byStructural Formula (IA) or (I), wherein:

R¹ is —H.

R² is ——H, —CH₃, —CH₂O—H, or -NH₂. Specifically, R² is ——H, or —CH₂OH.

R³ is ——H, —F, —Cl, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. Alternatively, R³ is——H, —F, or —Cl.

Z¹ is ——H, —F, or —Cl.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Z³ is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; iv) an optionallysubstituted, 4-7 membered non-aromatic heterocycle; v))an optionallysubstituted phenyl group; vi) an optionally substituted 5-6 memberedheteroaryl ring; or optionally, together with R and the nitrogen atom towhich it is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, —NRCO(C₁-C₄ alkyl), —CONR(C₁-C₄ alkyl), —NRCO₂(C₁-C₄ alkyl), aC₃-C₇ non-aromatic carbocycle optionally substituted with one or moreinstances of J^(E1), a 4-7 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1); and a phenyloptionally substituted with one or more instances of J^(E1); and

wherein each of said carbocycle, heterocycle, phenyl and heteroaryrepresented by R⁵ is independently and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

The remaining variables, including R⁴ that includes a spiro ringrepresented by rings E and F, or a bridged ring represented by ringsG1-G5, are each and independently as described in any one of thepreceeing four embodiments.

In yet another embodiment, the compounds are presented by StructuralFormula (IA) or (I), wherein values of the variabels are each andindependently as described in the preceeding embodiment, except:

Z² is —H;

Z³ is —H;

R⁵ is independently: i) —H or ii) a C₁-C₆-alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —CO₂H, C₃-C₈non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl,and 5-6 membered heteroaryl;

wherein each of said alkyl groups referred to in the substituents of theC₁-C₆-alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; and

wherein each of said carbocycle, phenyl, heterocycle, and heteroarylreferred to in the substituents of the C₁-C₆—alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

In yet another embodiment, each of rings E, G1-G5 is independently andoptionally substituted with onr or more substituents selected from thegroup consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and CO₂R^(b); wherein each of said alkyl groups is optionallyand independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, each of rings E, G1-G5 is independently and optionallysubstituted with onr or more substituents selected from the groupconsisting of halogen, cyano, hydroxy, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl),—C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁-C₄ alkyl).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts thereof,wherein:

R⁴ is:

Ring A is a non-aromatic, 5-10 membered, bridged carbocylce orheterocycle, or ring A and R⁸ optionally form a non-aromatic, 5-10membered, bridged carbocycle or heterocycle, or ring A and R⁹ optionallyform a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle,or ring A and R¹¹ optionally form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, wherein each of said carbocycle isindependently and optionally substituted with one or more instances ofJ^(A) and wherein each carbocycle is independently and optionallysubstituted with one or more instances of J^(B).

R¹ is —H.

R² is ——H, —CH₃, —CH₂O—H, or -NH₂. Specifically, R² is ——H, or —CH₂OH.

R³ is ——H, —F, —Cl, C₁-4 alkyl (e.g., —CH₃ or —C₂H₅), or C₁₋₄ haloalkyl(e.g., —CF₃).

Alternatively, R³ is ——H, —F, or —Cl.

Z¹ is ——H, —F, or —Cl.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Z³ is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Q² is independently —O—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —P(O)(OR)O—,—OP(O)(OR^(a))O—, —P(O)₂O—, —CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—.

Y¹ is —O—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—, —NRC(O)—,—NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, or —CO₂SO₂-.

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; iv) an optionallysubstituted, 4-7 membered non-aromatic heterocycle; v))an optionallysubstituted phenyl group; vi) an optionally substituted 5-6 memberedheteroaryl ring; or optionally, together with R and the nitrogen atom towhich it is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), —C₁-C₄alkoxy, —NRCO(C₁-C₄ alkyl), —CONR(C₁-C₄ alkyl), —NRCO₂(C₁-C₄ alkyl), aC₃-C₇ non-aromatic carbocycle optionally substituted with one or moreinstances of J^(E1), a 4-7 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1); and a phenyloptionally substituted with one or more instances of J^(E1);

wherein each of said carbocycle, heterocycle, phenyl and heteroaryrepresented by R⁵ is independently and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and—C₁-C₄ alkoxy.

Each of R⁸ and R⁹ is independently ——H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R¹¹, R¹², R¹³, and R¹⁴ are each independently ——H, halogen, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, and C₁-C₆alkoxy.

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂, C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆-alkyl), —OC(O)(C₁-C₆ alkyl),—NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), and —CO₂R^(b);wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

n is 0 or 1.

x is 0 or 1.

The remaining variables are each and independently as described above inany set of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Each of rings G1-G4 is independently a 5-10 membered non-aromaticbridged carbocycle optionally further substituted with one or moreinstances of J^(A), and ring G5 is a 5-10 membered non-aromatic bridgedheterocycle optionally further substituted with one or more instances ofJ^(B).

X is —O—, —S—, or —NR^(g)—.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently ——H, halogen, —O—H,C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)(C₁-C₆—alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl).

R^(g) is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy.

q is 0, 1 or 2.

r is 1 or 2.

The remaining variables are each and independently as described above inthe preceeding paragraph.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts thereof,wherein the variables are each and independently as described above inthe preceeding paragraph except those described below:

R¹ is —H.

R² is —H.

R³ is ——H, —F, —Cl, C₁-4 alkyl, or C₁₋₄ haloalkyl. Alternatively, R³ is——H, —F, or —Cl.

Z¹ is ——H, —F, or

Z² is —H.

Z³ is —H.

X is —O—.

R⁵ is ——H, an optionally substituted C₁-C₆ alkyl, or optionallysubstituted phenyl.

Each R⁸ is independently ——H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —O(C₁-C₄ alkyl).

Each of R⁹, R¹³, and R¹⁴ is independently —H or C₁-C₄ alkyl.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently ——H, halogen, —O—H,C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆ alkyl, and —O(C₁-C₆ alkyl). Specifically R²¹,R²², R²³, R²⁴, and R²⁵ are each independently ——H, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

Each rings G1-G5 are independently and optionally substituted with oneor more substituents selected from the group consisting of halogen,cyano, hydroxy, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆alkyl), C₁-C₄ alkyl that is optionally substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy, andC₁-C₄ alkoxy.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-V (hereinafter reference to Structural FormulaeI-IV includes Structural Formulae I, IA, II, III, IV, V, and VI) andXI(A)-XIV (hereinafter reference to Structural Formulae XI(A)-XIVincludes Structural Formulae XIA, XIB, XIIA, XIIB, XIII, and XIV),wherein values of the variables therein are independently as describedabove in any embodiments except that R³ is C₁₋₆ alkyl, such as methyl orethyl.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-V and XI(A)-XIV, wherein values of the variablestherein are independently as described above in any embodimentsdescribed above, except that x is 0.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values ofthe variables therein are independently as described above in anyembodiments described above, except that ring A is bridged.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values ofthe variables therein are independently as described above in anyembodiments described above, except that Q² is independently —C(═NR)—,—C(═NR)NR—, —NRC(═NR)NR—, —CO₂-, —OC(O)—, —C(O)NR—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-, —OC(O)NR—, —S(O)—,—SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, —CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—, or alternatively, Q² isindependently —CO₂-, —OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—,—NRC(O)—, —NRC(O)NR—, —NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-,—SO₂N(R)-, —NRSO₂NR—, —P(O)(OR)O—, —OP(O)(OR^(a))O—, —P(O)₂O—, —CO₂SO₂-,or —(CR⁶R⁷)_(p)—Y¹—.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-V and XI(A)-XIV, wherein values of the variablestherein are independently as described above in any embodimentsdescribed above, provided that when Q² is —O—or —NR—, then ring A isfurther substituted with J^(A) other than —H; and provided that if Q³ is—C(O)—, then R⁵ is a substituted C₁-C₆ aliphatic group; an optionallysubstituted C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; optionally substituted, 4-8membered non-aromatic heterocycle; or an optionally substituted 5-10membered heteroaryl group. In a specific embodiment, when Q² is —O—or—NR—, then ring A is further substituted with J^(A) other than —H at thegeminal position to -Q²R⁵.

In yet another embodiment, the present invention is directed to the useof any compound selected from the compounds depicted in FIGS. 3, 4, 5,6, 7, and 8, or a pharmaceutically acceptable salt thereof, for any ofthe uses described above.

In some embodiments, the compounds are represented by any one ofStructural Formulae I-V and XI(A)-XIV, and the variables are eachindependently as depicted in the compounds of FIGS. 1-8.

In yet another embodiment, the present invention is directed to the useof a compound described in any one of the embodiments, including varioussets of variables, for Structural Formulae I-V and XI(A)-XIV describedabove, or a pharmaceutically acceptable salt thereof, for any of theuses described above, provided that when R³ is —Cl, Z¹ is —F, and Z² is——H, then R⁴ is not 2-NH₂-cyclohexyl.

In yet another embodiment, the compounds described herein orpharmaceutically acceptable salts thereof can be used to reduce viraltitre in a biological sample (e.g. an infected cell culture) or inhumans (e.g. lung viral titre in a patient).

The terms “influenza virus mediated condition”, “influenza infection”,or “Influenza”, as used herein, are used interchangeable to mean thedisease caused by an infection with an influenza virus.

Influenza is an infectious disease that affects birds and mammals causedby influenza viruses. Influenza viruses are RNA viruses of the familyOrthomyxoviridae, which comprises five genera: Influenzavirus A,Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus.Influenzavirus A genus has one species, influenza A virus which can besubdivided into different serotypes based on the antibody response tothese viruses: H₁N1, H₂N2, H₃N2, H₅N1, H₇N7, H₁N2, H₉N2, H₇N2 , H₇N3 andH₁₀N7. Influenzavirus B genus has one species, influenza B virus.Influenza B almost exclusively infects humans and is less common thaninfluenza A. Influenzavirus C genus has one species, Influenzavirus Cvirus, which infects humans and pigs and can cause severe illness andlocal epidemics. However, Influenzavirus C is less common than the othertypes and usually seems to cause mild disease in children.

In some embodiments of the invention, influenza or influenza viruses areassociated with Influenzavirus A or B. In some embodiments of theinvention, influenza or influenza viruses are associated withInfluenzavirus A. In some specific embodiments of the invention,Influenzavirus A is H₁N1, H₂N2, H₃N2 or H₅N1.

In humans, common symptoms of influenza are chills, fever, pharyngitis,muscle pains, severe headache, coughing, weakness, and generaldiscomfort. In more serious cases, influenza causes pneumonia, which canbe fatal, particularly in young children and the elderly. Although it isoften confused with the common cold, influenza is a much more severedisease and is caused by a different type of virus. Influenza canproduce nausea and vomiting, especially in children, but these symptomsare more characteristic of the unrelated gastroenteritis, which issometimes called “stomach flu” or “24-hour flu”.

Symptoms of influenza can start quite suddenly one to two days afterinfection. Usually the first symptoms are chills or a chilly sensation,but fever is also common early in the infection, with body temperaturesranging from 38-39° C. (approximately 100-103° F.). Many people are soill that they are confined to bed for several days, with aches and painsthroughout their bodies, which are worse in their backs and legs.Symptoms of influenza may include: body aches, especially joints andthroat, extreme coldness and fever, fatigue, Headache, irritatedwatering eyes, reddened eyes, skin (especially face), mouth, throat andnose, abdominal pain (in children with influenza B). Symptoms ofinfluenza are non-specific, overlapping with many pathogens(“influenza-like illness). Usually, laboratory data is needed in orderto confirm the diagnosis.

The terms, “disease”, “disorder”, and “condition” may be usedinterchangeably here to refer to an influenza virus mediated medical orpathological condition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),specifically a “mammal” including a non-primate (e.g., a cow, pig,horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and aprimate (e.g., a monkey, chimpanzee and a human), and more specificallya human. In one embodiment, the subject is a non-human animal such as afarm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog,cat, guinea pig or rabbit). In a preferred embodiment, the subject is a“human”.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof

As used herein, “multiplicity of infection” or “MOI” is the ratio ofinfectious agents (e.g. phage or virus) to infection targets (e.g.cell). For example, when referring to a group of cells inoculated withinfectious virus particles, the multiplicity of infection or MOI is theratio defined by the number of infectious virus particles deposited in awell divided by the number of target cells present in that well.

As used herein the term “inhibition of the replication of influenzaviruses” includes both the reduction in the amount of virus replication(e.g. the reduction by at least 10%) and the complete arrest of virusreplication (i.e., 100% reduction in the amount of virus replication).In some embodiments, the replication of influenza viruses are inhibitedby at least 50%, at least 65%, at least 75%, at least 85%, at least 90%,or at least 95%.

Influenza virus replication can be measured by any suitable method knownin the art. For example, influenza viral titre in a biological sample(e.g. an infected cell culture) or in humans (e.g. lung viral titre in apatient) can be measured. More specifically, for cell based assays, ineach case cells are cultured in vitro, virus is added to the culture inthe presence or absence of a test agent, and after a suitable length oftime a virus-dependent endpoint is evaluated. For typical assays, theMadin-Darby canine kidney cells (MDCK) and the standard tissue cultureadapted influenza strain, A/Puerto Rico/8/34 can be used. A first typeof cell assay that can be used in the invention depends on death of theinfected target cells, a process called cytopathic effect (CPE), wherevirus infection causes exhaustion of the cell resources and eventuallysis of the cell. In the first type of cell assay, a low fraction ofcells in the wells of a microtiter plate are infected (typically 1/10 to1/1000), the virus is allowed to go through several rounds ofreplication over 48-72 hours, then the amount of cell death is measuredusing a decrease in cellular ATP content compared to uninfectedcontrols. A second type of cell assay that can be employed in theinvention depends on the multiplication of virus-specific RNA moleculesin the infected cells, with RNA levels being directly measured using thebranched-chain DNA hybridization method (bDNA). In the second type ofcell assay, a low number of cells are initially infected in wells of amicrotiter plate, the virus is allowed to replicate in the infectedcells and spread to additional rounds of cells, then the cells are lysedand viral RNA content is measured. This assay is stopped early, usuallyafter 18-36 hours, while all the target cells are still viable. ViralRNA is quantitated by hybridization to specific oligonucleotide probesfixed to wells of an assay plate, then amplification of the signal byhybridization with additional probes linked to a reporter enzyme.

As used herein a “viral titer (or titre)” is a measure of virusconcentration. Titer testing can employ serial dilution to obtainapproximate quantitative information from an analytical procedure thatinherently only evaluates as positive or negative. The titer correspondsto the highest dilution factor that still yields a positive reading; forexample, positive readings in the first 8 serial twofold dilutionstranslate into a titer of 1:256. A specific example is viral titer. Todetermine the titer, several dilutions will be prepared, such as 10⁻¹,10⁻², 10⁻³, . . . , 10⁻⁸. The lowest concentration of virus that stillinfects cells is the viral titer.

As used herein, the terms “treat”, “treatment” and “treating” refer toboth therapeutic and prophylactic treatments. For example, therapeutictreatments includes the reduction or amelioration of the progression,severity and/or duration of influenza viruses mediated conditions, orthe amelioration of one or more symptoms (specifically, one or morediscernible symptoms) of influenza viruses mediated conditions,resulting from the administration of one or more therapies (e.g., one ormore therapeutic agents such as a compound or composition of theinvention). In specific embodiments, the therapeutic treatment includesthe amelioration of at least one measurable physical parameter of aninfluenza virus mediated condition. In other embodiments the therapeutictreatment includes the inhibition of the progression of an influenzavirus mediated condition, either physically by, e.g., stabilization of adiscernible symptom, physiologically by, e.g., stabilization of aphysical parameter, or both. In other embodiments the therapeutictreatment includes the reduction or stabilization of influenza virusesmediated infections. Antiviral drugs can be used in the communitysetting to treat people who already have influenza to reduce theseverity of symptoms and reduce the number of days that they are sick.

The term “chemotherapy” refers to the use of medications, e.g. smallmolecule drugs (rather than “vaccines”) for treating a disorder ordisease.

The terms “prophylaxis” or “prophylactic use” and “prophylactictreatment” as used herein, refer to any medical or public healthprocedure whose purpose is to prevent, rather than treat or cure adisease. As used herein, the terms “prevent”, “prevention” and“preventing” refer to the reduction in the risk of acquiring ordeveloping a given condition, or the reduction or inhibition of therecurrence or said condition in a subject who is not ill, but who hasbeen or may be near a person with the disease. The term“chemoprophylaxis” refers to the use of medications, e.g. small moleculedrugs (rather than “vaccines”) for the prevention of a disorder ordisease.

As used herein, prophylactic use includes the use in situations in whichan outbreak has been detected, to prevent contagion or spread of theinfection in places where a lot of people that are at high risk ofserious influenza complications live in close contact with each other(e.g. in a hospital ward, daycare center, prison, nursing home, etc). Italso includes the use among populations who require protection from theinfluenza but who either do not get protection after vaccination (e.g.due to weak immunse system), or when the vaccine is unavailable to them,or when they cannot get the vaccine because of side effects. It alsoincludes use during the two weeks following vaccination, since duringthat time the vaccine is still ineffective. Prophylactic use may alsoinclude treating a person who is not ill with the influenza or notconsidered at high risk for complications, in order to reduce thechances of getting infected with the influenza and passing it on to ahigh-risk person in close contact with him (for instance, healthcareworkers, nursing home workers, etc).

According to the US CDC, an influenza “outbreak” is defined as a suddenincrease of acute febrile respiratory illness (AFRI) occurring within a48 to 72 hour period, in a group of people who are in close proximity toeach other (e.g. in the same area of an assisted living facility, in thesame household, etc) over the normal background rate or when any subjectin the population being analyzed tests positive for influenza. One caseof confirmed influenza by any testing method is considered an outbreak.

A “cluster” is defined as a group of three or more cases of AFRIoccurring within a 48 to 72 hour period, in a group of people who are inclose proximity to each other (e.g. in the same area of an assistedliving facility, in the same household, etc).

As used herein, the “index case”, “primary case” or “patient zero” isthe initial patient in the population sample of an epidemiologicalinvestigation. When used in general to refer to such patients inepidemiological investigations, the term is not capitalized. When theterm is used to refer to a specific person in place of that person'sname within a report on a specific investigation, the term iscapitalized as Patient Zero. Often scientists search for the index caseto determine how the disease spread and what reservoir holds the diseasein between outbreaks. Note that the index case is the first patient thatindicates the existence of an outbreak. Earlier cases may be found andare labeled primary, secondary, tertiary, etc.

In one embodiment, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, having apredisposition to complications resulting from infection by an influenzavirus. The term “pre-emptive” as used herein as for example inpre-emptive use, “pre-emptively”, etc, is the prophylactic use insituations in which an “index case” or an “outbreak” has been confirmed,in order to prevent the spread of infection in the rest of the communityor population group.

In another embodiment, the methods of the invention are applied as a“pre-emptive” measure to members of a community or population group,specifically humans, in order to prevent the spread of infection.

As used herein, an “effective amount” refers to an amount sufficient toelicit the desired biological response. In the present invention thedesired biological response is to inhibit the replication of influenzavirus, to reduce the amount of influenza viruses or to reduce orameliorate the severity, duration, progression, or onset of a influenzavirus infection, prevent the advancement of an influenza virusesinfection, prevent the recurrence, development, onset or progression ofa symptom associated with an influenza virus infection, or enhance orimprove the prophylactic or therapeutic effect(s) of another therapyused against influenza infections. The precise amount of compoundadministered to a subject will depend on the mode of administration, thetype and severity of the infection and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When co-administered with otheranti viral agents, e.g., when co-administered with an anti-influenzamedication, an “effective amount” of the second agent will depend on thetype of drug used. Suitable dosages are known for approved agents andcan be adjusted by the skilled artisan according to the condition of thesubject, the type of condition(s) being treated and the amount of acompound described herein being used. In cases where no amount isexpressly noted, an effective amount should be assumed. For example,compounds described herein can be administered to a subject in a dosagerange from between approximately 0.01 to 100 mg/kg body weight/day fortherapeutic or prophylactic treatment.

Generally, dosage regimens can be selected in accordance with a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the renal andhepatic function of the subject; and the particular compound or saltthereof employed, the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The skilled artisan canreadily determine and prescribe the effective amount of the compoundsdescribed herein required to treat, to prevent, inhibit (fully orpartially) or arrest the progress of the disease.

Dosages of the compounds described herein can range from between about0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kgbody weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1to about 25 mg/kg body weight/day. It is understood that the totalamount per day can be administered in a single dose or can beadministered in multiple dosing, such as twice a day (e.g., every 12hours), tree times a day (e.g., every 8 hours), or four times a day(e.g., every 6 hours).

For therapeutic treatment, the compounds described herein can beadministered to a patient within, for example, 48 hours (or within 40hours, or less than 2 days, or less than 1.5 days, or within 24 hours)of onset of symptoms (e.g., nasal congestion, sore throat, cough, aches,fatigue, headaches, and chills/sweats). The therapeutic treatment canlast for any suitable duration, for example, for 5 days, 7 days, 10days, 14 days, etc. For prophylactic treatment during a communityoutbreak, the compounds described herein can be administered to apatient within, for example, 2 days of onset of symptoms in the indexcase, and can be continued for any suitable duration, for example, for 7days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Various types of administration methods can be employed in theinvention, and are described in detail below under the section entitled“Administration Methods.”

Combination Therapy

An effective amount can be achieved in the method or pharmaceuticalcomposition of the invention employing a compound of any one ofStructural Formulae I-V (e.g., Structural Formulae I, IA, II, III, IVand V) and XI(A)-XIV (e.g., Structural Formulae XIA, XIB, XIIA, XIIB,XIII, and XIV) or a pharmaceutically acceptable salt or solvate (e.g.,hydrate) thereof alone or in combination with an additional suitabletherapeutic agent, for example, an antiviral agent or a vaccine. When“combination therapy” is employed, an effective amount can be achievedusing a first amount of a compound of any one of Structural Formulae I-Vand XI(A)-XIV, or a pharmaceutically acceptable salt or solvate (e.g.,hydrate) thereof, and a second amount of an additional suitabletherapeutic agent (e.g. an antiviral agent or vaccine).

In another embodiment of this invention, the compound of any one ofStructural Formulae I-V and XI(A)-XIV, and the additional therapeuticagent, are each administered in an effective amount (i.e., each in anamount which would be therapeutically effective if administered alone).In another embodiment, the compound of any one of Structural FormulaeI-V and XI(A)-XIV, and the additional therapeutic agent, are eachadministered in an amount which alone does not provide a therapeuticeffect (a sub-therapeutic dose). In yet another embodiment, the compoundof any one of Structural Formulae I-V and XI(A)-XIV can be administeredin an effective amount, while the additional therapeutic agent isadministered in a sub-therapeutic dose. In still another embodiment, thecompound of any one of Structural Formulae I-V and XI(A)-XIV can beadministered in a sub-therapeutic dose, while the additional therapeuticagent, for example, a suitable cancer-therapeutic agent is administeredin an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Coadministration encompasses administration of the first and secondamounts of the compounds of the coadministration in an essentiallysimultaneous manner, such as in a single pharmaceutical composition, forexample, capsule or tablet having a fixed ratio of first and secondamounts, or in multiple, separate capsules or tablets for each. Inaddition, such coadministration also encompasses use of each compound ina sequential manner in either order.

In one embodiment, the present invention is directed to methods ofcombination therapy for inhibiting Flu viruses replication in biologicalsamples or patients, or for treating or preventing Influenza virusinfections in patients using the compounds or pharmaceuticalcompositions of the invention of any one of Structural Formulae I-V andXI(A)-XIV. Accordingly, pharmaceutical compositions of the inventionalso include those comprising an inhibitor of Flu virus replication ofthis invention in combination with an anti-viral compound exhibitinganti-Influenza virus activity.

Methods of use of the compounds and compositions of the invention alsoinclude combination of chemotherapy with a compound or composition ofany one of Structural Formulae I-V and XI(A)-XIV or with a combinationof a compound or composition of this invention with another anti-viralagent and vaccination with a Flu vaccine.

When co-administration involves the separate administration of the firstamount of a compound of any of Structural Formulae I-V and XI(A)-XIV anda second amount of an additional therapeutic agent, the compounds areadministered sufficiently close in time to have the desired therapeuticeffect. For example, the period of time between each administrationwhich can result in the desired therapeutic effect, can range fromminutes to hours and can be determined taking into account theproperties of each compound such as potency, solubility,bioavailability, plasma half-life and kinetic profile. For example, acompound of any one of Structural Formulae I-V and XI(A)-XIV and thesecond therapeutic agent can be administered in any order within about24 hours of each other, within about 16 hours of each other, withinabout 8 hours of each other, within about 4 hours of each other, withinabout 1 hour of each other or within about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound of the invention) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy (e.g., a prophylactic or therapeuticagent such as an anti-cancer agent) to a subject.

It is understood that the method of co-administration of a first amountof a compound of any one of Structural Formulae I-V and XI(A)-XIV and asecond amount of an additional therapeutic agent can result in anenhanced or synergistic therapeutic effect, wherein the combined effectis greater than the additive effect that would result from separateadministration of the first amount of the compound of any one ofStructural Formulae I-V and XI(A)-XIV and the second amount of theadditional therapeutic agent.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent), which is more effective than the additive effects ofthe therapies. A synergistic effect of a combination of therapies (e.g.,a combination of prophylactic or therapeutic agents) can permit the useof lower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject. The ability to utilizelower dosages of a therapy (e.g., a prophylactic or therapeutic agent)and/or to administer said therapy less frequently can reduce thetoxicity associated with the administration of said therapy to a subjectwithout reducing the efficacy of said therapy in the prevention,management or treatment of a disorder. In addition, a synergistic effectcan result in improved efficacy of agents in the prevention, managementor treatment of a disorder. Finally, a synergistic effect of acombination of therapies (e.g., a combination of prophylactic ortherapeutic agents) may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapy alone.

When the combination therapy using compounds of the present invention ofany one of Structural Formulae I-V and XI(A)-XIV is in combination witha Flu vaccine, both therapeutic agents can be administered so that theperiod of time between each administration can be longer (e.g. days,weeks or months).

The presence of a synergistic effect can be determined using suitablemethods for assessing drug interaction. Suitable methods include, forexample, the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loeweadditivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median-effect equation (Chou, T. C. andTalalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equationreferred to above can be applied with experimental data to generate acorresponding graph to aid in assessing the effects of the drugcombination. The corresponding graphs associated with the equationsreferred to above are the concentration-effect curve, isobologram curveand combination index curve, respectively.

Specific examples that can be co-administered with a compound describedherein include neuraminidase inhibitors, such as oseltamivir (Tamiflu®)and Zanamivir (Rlenza®), viral ion channel (M2 protein) blockers, suchas amantadine (Symmetrel®) and rimantadine (Flumadine®), and antiviraldrugs described in WO 2003/015798, including T-705 under development byToyama Chemical of Japan. (See alsoRuruta et al., Antiviral Reasearch,82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novelbroad-spectrum inhibitors of RNA viral infections.”) In someembodiments, the compounds described herein can be co-administerd with atraditional influenza vaccine.

Compounds of the Invention

Another aspect of the present invention is generally related tocompounds. In one embodiment, the present invention is generally relatedto compounds represented by Structural Formula (IA) or (I), orpharmaceutically acceptable salts thereof:

A first subset of variables of Structural Formulae (I) and (IA) for thecompounds of the invention is as follows:

R¹ is ——H, C₁-C₆ alkyl, —S(O)₂-R″ or —C(O)OR″. Specifically, R¹ is —H orS(O)₂-R″. Specifically, R¹ is —H or —S(O)₂-(phenyl), wherein the phenylis optionally substituted with one or more selected from the groupconsisting of C₁-C₆ alkyl and C₁-C₆ haloalkyl. More specifically, thephenyl is optionally substituted with one or more selected from thegroup consisting of —CH₃ and —CF₃ (e.g., at its para position).Specifically, R¹ is —H or C₁₋₆ alkyl. Specifically, R¹ is —H.

R⁴ is:

R″ is independently: i) a C₁-C₆-alkyl optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or ii) a C₃-C₆ carbocyclicgroup, a 5-6 membered heteroaryl group, or a phenyl group, eachoptionally and independently being substituted with one ore moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, nitro, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₁-C₆hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy. Specifically, R″ is independently an optionallysubstituted, 5-6 membered heteroaryl group, or an optionally substitutedphenyl group. Specifically, R″ is independently a phenyl groupoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl and C₁-C₆ haloalkyl.

Values of Z¹, Z², Z³, Q¹, Q², Q³, Y¹, rings A-D, R*, R, R′, R², R³, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(a), R^(b), R^(c), R^(d),J^(A), J^(B), J^(C1), J^(D1) and J^(E1), including specific values andsubstituents therefor, are each and independently as described above inthe first set of variables of Structural Formulae (IA) and (I) for themethods of the invention.

Value p is independently 1, 2, 3 or 4. Specifically, p is independently1 or 2.

When rings A and B are 3-6-membered, n and m are each independently 0 or1; and k is independently 0, 1 or 2. Alternatively, when rings A and Bare 7-10-membered, n and m, are each independently 0, 1 or 2; and k isindependently 0, 1 or 2.

Values x and y are each independently 0, 1 or 2.

Value z is 1 or 2.

It is provided that if Y¹ is a bond, then R⁵ is neither ——H, nor anunsubstituted C₁-C₆ aliphatic group. Specifically, if Y¹ is a bond, thenR⁵ is a substituted C₁-C₆ aliphatic group; an optionally substitutedC₃-C₈ non-aromatic carbocycle; an optionally substituted 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; or an optionally substituted, 5-10 memberedheteroary group. Specifically, the C₁-C₆ aliphatic group represented byR⁵ is substituted with one or more instances of J^(C1), wherein J^(C1)is independently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂N(R)R^(b); —NRSO₂R^(b); and—NRSO₂NRR^(b); or optionally two J^(C1) and two J^(D1), respectively,together with the atoms to which they are attached, independently form a5-7-membered ring that is optionally substituted with one or moreinstances of J^(E1), and fused to the respective ring to which they areattached.

It is provided that if Q² and Q³ are each and independently a bond, thenR⁵ is an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group. Specifically, ifQ² and Q³ are each and independently a bond, then R⁵ is an optionallysubstituted C₃-C₈ non-aromatic carbocycle; or an optionally substituted,4-8 membered non-aromatic heterocycle. Alternatively, it is providedthat if rings A and B each and independently 5- or 6-membered, R¹ and R²are both ——H, R³ is —Cl, Z² is ——H, and Z¹ is —F, then Q²-R⁵ and Q³-R⁵,respectively, are not —H; and it is provided that the ring B-Q³-R⁵moiety is not N-methyl-3-pyrrolidinyl

A second subset of variables of Structural Formulae (IA) and (I) for thecompounds of the invention is as follows:

R² is —H or CH₃.

R³ is ——H, —Cl, —F, —Br, —CN, —CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R⁴ is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables of Structural Formulae(IA) and (I).

A third subset of variables of Structural Formula I for the compounds ofthe invention is as follows:

R² is —H or —CH₃.

R³ is ——H, —F, —Cl, —CF₃, -NH₂, -NH(CH₃), or —N(CH₃)₂.

R⁴ is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables of Structural Formulae(IA) and (I).

A fourth subset of variables of Structural Formulae (IA) and (I)for thecompounds of the invention is as follows:

R² is —H or CH₃.

R³ is ——H, —F, or —Cl.

R⁴ is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, are each and independently as described abovefor the first subset of variables of Structural Formulae (IA) and (I).

A fifth subset of variables of Structural Formulae (IA) and (I) for thecompounds of the invention is as follows:

R² is —H.

R³ is —H or —Cl.

R⁴ is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables of Structural Formulae(IA) and (I).

A sixth subset of variables of Structural Formulae (IA) and (I)for thecompounds of the invention is as follows:

Each of R², R³ and R⁴ is independently as described in the first subset,second subset, third subset, fourth subset, or fifth subset, ofvariables of Structural Formulae (IA) and (I).

Z¹ is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —F, —Cl, —CN, —CO₂H, —CO₂(C₁-C₆alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), or —CON(C₁-C₆ alkyl)₂; and Z² is——H, —C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or -N(C₁-C₆alkyl)₂; wherein each of said alkyl groups (e.g., represented by C₁-C₆alkyl, —O(C₁-C₆ alkyl), —CO₂(C₁-C₆ alkyl), -NH(C₁-C₆ alkyl), and-N(C₁-C₆ alkyl)₂) is optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables of Structural Formulae(IA) and (I).

A seventh subset of variables of Structural Formulae (IA) and (I) forthe compounds of the invention is as follows:

Each of R², R³ and R⁴ is independently as described in the first subset,second subset, third subset, fourth subset, or fifth subset, ofvariables of Structural Formulae (IA) and (I).

Z¹ is ——H, —F, —Cl, —CF₃, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), or —CN; and Z²is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups (e.g., representedby C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)₂)is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables.

An eighth subset of variables of Structural Formulae (IA) and (I) forthe compounds of the invention is as follows:

Each of R², R³ and R⁴ is independently as described in the first subset,second subset, third subset, fourth subset, or fifth subset, ofvariables of Structural Formulae (IA) and (I).

Z¹ is ——H, —F, —Cl, C₁-C₄ haloalkyl (e.g, —CF₃), C₁-C₄ alkyl, —O(C₁-C₄alkyl), or —CN.

Z² is —H or a C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ CO₂H, CO₂(C₁-C₄ alkyl),and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provios are each and independently asdescribed above for the first subset of variables.

A ninth subset of variables of Structural Formulae (IA) and (I) for thecompounds of the invention is as follows:

Each of R², R³ and R⁴ is independently as described in the first subset,second subset, third subset, fourth subset, or fifth subset, ofvariables of Structural Formulae (IA) and (I).

Z¹ is ——H, —F, —Cl, —CF₃, —CH₃, or —CN.

Z² is —H or a C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first subset of variables of Structural Formulae(IA) and (I).

In a tenth subset of variables of Structural Formulae (IA) and (I) forthe compounds of the invention, the variables of Structural Formulae(IA) and (I), including specific values, are each and independently asdescribed above for the first, second, third, fourth, fifth, sixth,seventh, eighth, or ninth subset of variables of Structural Formulae(IA) and (I); and where applicable:

each R* independently is: i) —H; ii) C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; or iii) a 3-7 membered carbocyclic ringoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, and C₁-C₆ alkyl, whereineach alkyl is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkly), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy;and

R and R′ are each independently —H or C₁-C₆ alkyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, and —O(C₁-C₆ alkyl); or optionally R′, together withR⁵ and the nitrogen atom to which they are attached, forms a 5-7membered, non-aromatic, heterocyclic ring optionally substituted withone or more instances of J^(D1); and

R″ is independently a phenyl group optionally substituted with one ormore substituents independently selected from the group consisting ofC₁-C₆ alkyl and C₁-C₆ haloalkyl.

In an eleventh subset of variables of Structural Formulae (IA) and (I)for the compounds of the invention, the variables of Structural Formulae(IA) and (I), including specific values, are each and independently asdescribed above for the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, or tenth subset of variables of StructuralFormulae (IA) and (I); and where applicable:

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and

provided that if Q² and Q³ are each and independently a bond, then R⁵ isan optionally substituted C₃-C₈ non-aromatic carbocycle; an optionallysubstituted 6-10-membered carbocyclic aryl group; an optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted, 5-10 membered heteroary group.

In a twelfth subset of variables of Structural Formulae (IA) and (I) forthe compounds of the invention , the variables of Structural Formulae(IA) and (I), including specific values, are each and independently asdescribed above for the eleventh subset of variables of StructuralFormulae (IA) and (I); and the C₁-C₆ aliphatic group represented by R⁵,when Y¹ is a bond, is substituted with one or more instances of J^(C1),wherein J^(C1) is independently selected from: an optionallysubstituted, C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; an optionally substituted, 5-10membered heteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a);—NR^(b)R^(c); —C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b);—C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c);—C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b);—NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); or optionally two J^(C1) and twoJ^(D1), respectively, together with the atoms to which they areattached, independently form a 5-7-membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to therespective ring to which they are attached.

A thirteenth subset of variables of Structural Formulae (IA) and (I) isas follows:

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, and Q¹-R⁵; or optionally two J^(A)and two J^(B), respectively, together with the atom(s) to which they areattached, independently form a 5-7 membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to the ringto which they are attached.

Q¹ is independently a bond, —O—, —S—, —NR′—, —C(O)—, —CO₂-, —OC(O)—,—C(O)NR′—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂-, —OC(O)NR′—, —S(O)—, —SO₂-, —SO₂NR′—, —NRSO₂-, or NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), C(O)R^(b), C(O)OR^(b), —OC(O)R^(b),—NRC(O)R^(b), C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b),—OCONR^(b)R^(c), C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), and —NRSO₂NR^(c)R^(b), or optionally, twoJ^(C1) and two J^(D1), respectively, together with the atoms to whichthey are attached, independently form a 5-7-membered ring that isoptionally substituted with one or more instances of J^(E1), and fusedto the respective ring to which they are attached.

Values of the remaining variables of Structural Formulae (IA) and (I),including specific values, and provisos are each and independently asdescribed above for the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, or twelfth subset of variablesof Structural Formulae (IA) and (I).

In a fourteenth subset of variables of Structural Formulae (IA) and (I),values of the variables are independently as described above in theseventeenth set of variables of Structural Formulae (IA) and (I).

In a fifteenth subset of variables of Structural Formulae (IA) and (I),values of the variables are independently as described above in theeighteenth set of variables of Structural Formulae (IA) and (I).

In a sixteenth subset of variables of Structural Formulae (IA) and (I),values of the variables are independently as described above in thenineteenth set of variables of Structural Formulae (IA) and (I).

In some embodiments, the compounds are represented by Structural Formula(IA) or (I), or pharmaceutically acceptable salts thereof, wherein R¹ is—H or C₁₋₆ alkyl, and wherein values of the remaining variables areindependently as described above in any one of the subsets of variablesof Structural Formulae (IA) and (I).

In another embodiment, the present invention is generally related tocompounds represented by Structural Formula VI, or pharmaceuticallyacceptable salts thereof.

A first subset of variables of Structural Formula VI for the compoundsof this invention is as follows:

Z¹ is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —F, —Cl, —CN, —CO₂H, —CO₂(C₁-C₆alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), or —CON(C₁-C₆ alkyl)₂, wherein eachof said alkyl groups (e.g., representd by C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—CO₂(C₁-C₆ alkyl), —CONH(C₁-C₆ alkyl), and —CON(C₁-C₆ alkyl)₂) isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups (e.g., representedby C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)₂)is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), —CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formula VI, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae (IA) and(I).

A second subset of variables of Structural Formula VI for the compoundsof this invention is as follows:

Z¹ is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —F, —Cl, —CN, —CO₂H, —CO₂(C₁-C₆alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), or —CON(C₁-C₆ alkyl)₂, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂; wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

R³ is ——H, —Cl, —F, —Br, —CN, —CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

Values of the remaining variables of Structural Formula VI, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae (IA) and(I).

A third subset of variables of Structural Formula VI for the compoundsof this invention is as follows:

Z¹ is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —F, —Cl, —CN, —CO₂H, —CO₂(C₁-C₆alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), or —CON(C₁-C₆ alkyl)₂, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂; wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

R³ is ——H, —F, —Cl, —CF₃, -NH₂, -NH(CH₃), or —N(CH₃)₂. Specifically, R³is ——H, —Cl, or —F. Specifically, R³ is —Cl.

Values of the remaining variables of Structural Formula VI, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae (IA) and(I).

In a fourth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

In a fifth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the first, second, third, or fourthsubset of variables of Structural Formulae (IA) and (I); and whereapplicable:

provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H; and

provided that if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group.

In a sixth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the fifth subset; and the C₁-C₆aliphatic group represented by R⁵, when Q³ is —C(O)—, is substitutedwith one or more instances of J^(C1), wherein J^(C1) is independentlyselected from: an optionally substituted, C₃-C₈ non-aromatic carbocycle;an optionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; anoptionally substituted, 5-10 membered heteroaryl group; —OR^(b);—SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c); —C(O)R^(b); —C(O)OR^(b);—OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c);—NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b);—C(O)NR(OR^(b)); —SO₂NR_(c)R^(b); —NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); oroptionally two J^(C1) and two J^(D1), respectively, together with theatoms to which they are attached, independently form a 5-7-membered ringthat is optionally substituted with one or more instances of J^(E1), andfused to the respective ring to which they are attached.

In a seventh subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the first, second, third, or fourthsubset of variables of Structural Formulae (IA) and (I); and whereapplicable:

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and

provided that if Q² and Q³ are each and independently a bond, then R⁵ isan optionally substituted C₃-C₈ non-aromatic carbocycle; an optionallysubstituted 6-10-membered carbocyclic aryl group; an optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted, 5-10 membered heteroary group.

In an eighth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the seventh subset of variables ofStructural Formulae (IA) and (I); and

the C₁-C₆ aliphatic group represented by R⁵, when Y¹ is a bond, issubstituted with one or more instances of J^(C1), wherein J^(C1) isindependently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and—NRSO₂NR^(c)R^(b); or optionally two J^(C1) and two J^(D1),respectively, together with the atoms to which they are attached,independently form a 5-7-membered ring that is optionally substitutedwith one or more instances of J^(E1), and fused to the respective ringto which they are attached.

In a ninth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the first, second, third, or fourthsubset of variables of Structural Formulae (IA) and (I); and whereapplicable:

provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H;

provided that if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group;

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and provided thatif Q² and Q³ are each and independently a bond, then R⁵ is an optionallysubstituted C₃-C₈ non-aromatic carbocycle; an optionally substituted6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; or an optionally substituted, 5-10membered heteroary group.

In a tenth subset of variables of Structural Formula VI for thecompounds of this invention, values of the variables for StructuralFormula VI, including specific values, and provisos are each andindependently as described above in the ninth subset of variables ofStructural Formulae (IA) and (I); and

when Q³ is —C(O)—, or Y¹ is a bond, the C₁-C₆ aliphatic grouprepresented by R⁵ is substituted with one or more instances of J^(C1),wherein J^(C1) is independently selected from: an optionallysubstituted, C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; an optionally substituted, 5-10membered heteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a);—NR^(b)R^(c); C(O)R^(b); C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b);—C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c);—C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b);—NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); or optionally two J^(C1) and twoJ^(D1), respectively, together with the atoms to which they areattached, independently form a 5-7-membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to therespective ring to which they are attached.

In an eleventh subset of variables of Structural Formula VI, values ofthe variables for Structural Formula VI, including specific values, areeach and independently as described above in the thirteenth subset ofvariables of Structural Formulae (IA) and (I).

In another embodiment, the present invention is generally related tocompounds represented by any one of Structural Formulae II, III, IV andV, or pharmaceutically acceptable salts thereof:

A first subset of variables of Structural Formulae II, III, IV and V forthe compounds of the invention is as follows:

Each Q² is independently —O—, —S—, —NR′—, —C(O)—, —CO₂-, —OC(O)—,—C(O)NR′—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂-, —OC(O)NR′—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

Each Q³ is independently —C(O)—, —CO₂-, —C(O)NR′—, —SO₂-, —SO₂NR′—,—C(O)NRC(O)O—, or —(CR⁶R⁷)_(p)—Y¹—.

Z¹ is ——H, —F, —Cl, C₁-C₄ haloalkyl (e.g., —CF₃), C₁-C₄ alkyl, —O(C₁-C₄alkyl), or —CN.

Z² is ——H, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), or-N(C₁-C₆ alkyl)₂, wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C 4 alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

R³ is ——H, —Cl, —F, —Br, —CN, —CF₃, —O(C₁-C₄ alkyl), —O—H, -NH₂,-NH(C₁-C₄ alkyl) or -N(C₁-C₄ alkyl)₂. Specifically, R³ is ——H, —F, —Cl,—CF₃, -NH₂, -NH(CH₃), or —N(CH₃)₂. Specifically, R³ is ——H, —Cl, or —F.Specifically, R³ is —Cl.

Each R and R′ is independently —H or C₁-C₆alkyl.

Definitions of rings A-D of formulae II-V, including specific variables,are each and independently as described above for the first set ofvariables of Structural Formulae (IA) and (I), wherein each of rings A-Dis independently an optionally substituted, 4-7 membered ring. Values ofthe remaining variables of Structural Formulae II-V, including specificvalues, and provisos are each and independently as described above forthe first subset of variables of Structural Formulae (IA) and (I).

A second subset of variables of Structural Formulae II, III, IV and Vfor the compounds of the invention is as follows:

Z¹ is ——H, —F, —Cl, —CF₃, —CH₃, or —CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae II-V, includingspecific values and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae II-V.

A third subset of variables of Structural Formulae II, III, IV and V forthe compounds of the invention is as follows:

Z¹ is ——H, —F, or —CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae II-V.

A fourth subset of variables of Structural Formulae II, III, IV and Vfor the compounds of the invention is as follows:

Z¹ is ——H, —F, or —CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂,-NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

R³ is ——H, ——Cl or —F.

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae II-V.

A fifth subset of variables of Structural Formulae II, III, IV and V forthe compounds of the invention is as follows:

Z¹ is ——H, —F or —CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, alkyl, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl),and C₁-C₄ alkoxy.

R³ is ——H, —Cl, —F, —CF₃, -NH₂, -NH(CH₃), —N(CH₃)₂.

R⁶ and R⁷ are each independently —H or —CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently ——H, halogen, cyano, hydroxy, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl),-NH₂, -NH(C₁-C₄ alkyl) or —N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or —CH₃.

R¹¹ and R¹² are each independently —H or —CH₃.

R¹³ and R¹⁴ are each independently —H or —CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae II-V.

A sixth subset of variables of Structural Formulae II, III, IV and V forthe compounds of the invention is as follows:

Z¹ is ——H, —F or —CN.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂,-NH(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

R³ is ——H, ——Cl or —F.

R⁶ and R⁷ are each independently —H or CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently —H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or —CH₃.

R¹¹ and R¹² are each independently —H or —CH₃.

R¹³ and R¹⁴ are each independently —H or —CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae II-V.

In a seventh subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables, except for R⁶, R⁷, R⁸,R⁹, R¹¹, R¹², R¹³ and R¹⁴, of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove in the first, second, third, or fourth subset of variables ofStructural Formulae (IA) and (I).

R⁶ and R⁷ are each independently —H or C₁-C₄ alkyl, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently —H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,NH(C₁-C₄ alkyl) or —N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or C₁-C₄ alkyl.

R¹¹ and R¹² are each independently —H or C₁-C₄ alkyl.

R¹³ and R¹⁴ are each independently —H or C₁-C₄ alkyl, or together withthe carbon atoms to which they are attached they form a cyclopropanering

In an eighth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, and provisos are each and independentlyas described above in the first subset of variables of StructuralFormulae (IA) and (I).

In a ninth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh, oreighth subset of variables of Structural Formulae II-V; and whereapplicable:

provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H; and

provided that if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group.

In a tenth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the ninth subset of variables of Structural Formulae II-V; andwhere applicable:

when Q³ is —C(O)—, the C₁-C₆ aliphatic group represented by R⁵ issubstituted with one or more instances of J^(C1), wherein J^(C1) isindependently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and—NRSO₂NR^(c)R^(b); or optionally two J^(C1) and two J^(D1),respectively, together with the atoms to which they are attached,independently form a 5-7-membered ring that is optionally substitutedwith one or more instances of J^(E1), and fused to the respective ringto which they are attached.

In an eleventh subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh, oreighth subset of variables of Structural Formulae II-V; and whereapplicable:

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and

provided that if Q² and Q³ are each and independently a bond, then R⁵ isan optionally substituted C₃-C₈ non-aromatic carbocycle; an optionallysubstituted, 6-10-membered carbocyclic aryl group; an optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted, 5-10 membered heteroary group.

In a twelfth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the eleventh subset of variables of Structural Formulae II-V;and where applicable:

when Y¹ is a bond, the C₁-C₆ aliphatic group represented by R⁵ issubstituted with one or more instances of J^(C1), wherein J^(C1) isindependently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and—NRSO₂NR^(c)R^(b); or optionally two J^(C1) and two J^(D1),respectively, together with the atoms to which they are attached,independently form a 5-7-membered ring that is optionally substitutedwith one or more instances of J^(E1), and fused to the respective ringto which they are attached.

In a thirteenth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh, oreighth subset of variables of Structural Formulae II-V; and whereapplicable:

provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H;

provided that if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group.

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and provided thatif Q² and Q³ are each and independently a bond, then R⁵ is an optionallysubstituted C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; or an optionally substituted, 5-10membered heteroary group.

In a fourteenth subset of variables of Structural Formulae II-V for thecompounds of the invention, values for variables of Structural FormulaeII-V, including specific values, are each and independently as describedabove for the thirteenth subset of variables of Structural FormulaeII-V; and where applicable:

when Q³ is —C(O)—, or Y¹ is a bond, the C₁-C₆ aliphatic grouprepresented by R⁵ is substituted with one or more instances of J^(C1),wherein J^(C1) is independently selected from: an optionallysubstituted, C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; an optionally substituted, 5-10membered heteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a);—NR^(b)R^(c); —C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b);—C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c);—C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b);—NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); or optionally two J^(C1) and twoJ^(D1), respectively, together with the atoms to which they areattached, independently form a 5-7-membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to therespective ring to which they are attached.

A fifteenth subset of variables of Structural Formulae II-V is asfollows:

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, oxo, and Q¹-R⁵; or optionally two J^(A)and two J^(B), respectively, together with the atom(s) to which they areattached, independently form a 5-7 membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to the ringto which they are attached.

Q¹ is independently a bond, —O—, —S—, —NR—, —C(O)—, —CO₂-, —OC(O)—,—C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, or—(CR⁶R⁷)_(p)—Y¹—.

Q² is independently a bond, —O—, —S—, —NR—, —C(O)—, —CO₂-, —OC(O)—,—C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, or—(CR⁶R⁷)_(p)—Y¹—.

Q³ is independently a bond, —C(O)—, —CO₂-, —C(O)NR—, —SO₂-, —SO₂N(R)-,—C(O)NRC(O)O—or —(CR⁶R⁷)_(p)—Y¹—.

R⁵ is: i) —H; ii) a C₁-C₆ aliphatic group optionally substituted withone or more instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycle,or 6-10 membered carbocyclic aryl group, each optionally andindependently substituted with one or more instances of J^(C1); or iv) a4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroarylgroup, each optionally and independently substituted with one or moreinstances of J^(D1).

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), —NR^(b)R^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NRC(O)R^(b), —C(O)NR^(b)R^(c), —NRC(O)NR^(b)R^(c), —NRC(O)OR^(b),—OCONR^(b)R^(c), —C(O)NRCO₂R^(b), —NRC(O)NRC(O)OR^(b), —C(O)NR(OR^(b)),—SO₂NR^(c)R^(b), —NRSO₂R^(b), and —NRSO₂NR^(c)R^(b), or optionally, twoJ^(C1) and two J^(D1), respectively, together with the atoms to whichthey are attached, independently form a 5-7-membered ring that isoptionally substituted with one or more instances of J^(E1), and fusedto the respective ring to which they are attached.

Ring A is a C₃-C₈ non-aromatic carbocycle optionally and independentlyfurther substituted with one or more instances of J^(A).

Values of the remaining variables of Structural Formulae II-V, includingspecific values, and provisos are each and independently as describedabove for the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenthsubset of variables of Structural Formulae II-V.

In another embodiment, the present invention is generally related tocompounds of Structural Formula XI(A) or XI(B), or pharmaceuticallyacceptable salts thereof.

A first subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Each Q² is independently —O—, —S—, —NR′—, —C(O)—, —CO₂-, —OC(O)—,—C(O)NR′—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—,—NRCO₂-, —OC(O)NR′—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, or —(CR⁶R⁷)_(p)—Y¹—.

Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl,C₂-C₆ alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)(C₁-C₆-alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), and —CO₂R^(b); wherein each of said alkyl andalkenyl groups is optionally and independently substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C ₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy. Specifically, ring A is a 5-7 membered,non-aromatic carbocyclic ring optionally further substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl□, —CO₂H, and—CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, ring A is a 5-7 membered carbocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy,C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, —CO₂H, and —CO₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or —CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

Each R⁸ is independently —H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), —NH₂,—NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂.

Each R⁹ is independently —H or —CH₃.

R¹¹ and R¹² are each independently —H or —CH₃.

R¹³ and R¹⁴ are each independently —H or —CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R and R′ is independently —H or C₁-C₆ alkyl.

Provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A second subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Ring A, Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³ and R¹⁴,including specific values, and provisos are each and independently asdescribed above in the first subset of variables of Structural FormulaeXI(A) and XI(B).

Variable x is 0 or 1 and variable n is 0 or 1.

Values of the remaining variables of Structural Formulae XI(A) or XI(B),including specific values, and provisos are each and independently asdescribed above in the first subset of variables of Structural FormulaeXI(A) and XI(B).

A third subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Ring A, R, R′, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, and provisos are each and independently asdescribed above in the second subset of variables of Structural FormulaeXI(A) and XI(B).

Q² is —O—, —NR′—, —CO—, —CO₂-, —C(O)NR′—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OCONR′—, —NRSO₂, —SO₂NR′—, or —(CR⁶R⁷)_(p)—Y¹—. Specifically, Q² is—O—, —NH—, —N(CH₃)—, —C(O)—, —CO₂-, —C(O)NH—, —C(O)N(CH₃)—, —NHC(O)—,—N(CH₃)C(O)—, —NHC(O)NR′—, —N(CH₃)C(O)NR′—, —NHCO₂-, —N(CH₃)CO₂-,—OC(O)NR′—, -NHSO₂-, —N(CH₃)SO₂-, —SO₂NH—, —SO₂N(CH₃)—, or—(CR⁶R⁷)_(p)—Y¹—.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A fourth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Ring A, Q², R, R′, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x andn, including specific values, and provisos are each and independently asdescribed above in the third subset of variables of Structural FormulaeXI(A) and XI(B)

R⁵ is independently i) —H; ii) a C₁-C₆ aliphatic group (e.g.,C₁-C₆—alkyl or C₂-C₆ alkenyl group) optionally substituted with one ormore instances of J^(C1); iii) a C₃-C₈ non-aromatic carbocycleoptionally substituted with one or more instances of J^(C1); iv) aphenyl group optionally substituted with one or more instances ofJ^(C1); v) a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(D1) or vi) a 5-6 memberedheteroaryl ring optionally substituted with one or more instances ofJ^(D1).

Each J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a)—,—SO₂R^(a), -NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),—C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b).

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A fifth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, and provisos are each and independently asdescribed above in the fourth subset of variables of Structural FormulaeXI(A) and XI(B).

Ring A is optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl □, —CO₂H, and —CO₂(C₁-C₄ alkyl),wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of h halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,-NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

It is provided that if Q²-R⁵ is —OR⁵ or —NR′R⁵, then ring A is furthersubstituted with one or more instances of J^(A) other than —H.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (1).

A sixth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, and provisos are each and independently asdescribed above in the fifth subset of variables of Structural FormulaeXI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below

wherein each of rings A1-A27 is independently and optionally furthersubstituted with one or more substituents. Specifically, rings A5, A6,A21, A24, and A26 are each independently further substituted with one ormore instances of substituents other than H. Suitable substituents areas described above for ring A in the first subset of variables ofStructural Formulae XI(A) and XI(B).

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A seventh subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of the group —[CR¹³R^(14]) _(x)-ringA-Q²-R⁵, ring A, Q², R, R′,R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n, including specific values,and provisos are each and independently as described above in the sixthsubset of variables of Structural Formulae XI(A) and XI(B).

Each R⁵ is independently: i) —H; ii) a —C₁-C₆-aliphatic group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —CO₂H, C₃-C₈non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle,and 5-6 membered heteroaryl; or iii) a C₃-C₇ non-aromatic carbocycle, a4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 memberedheteroaryl ring, each of which is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁C₄ alkyl), -NH₂, —NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), and —CO₂H; whereineach of said alkyl groups for the substituents of the aliphatic group,carbocycle, heterocycle, phenyl and heteroaryl group represented by R⁵is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, andheteroaryl for the substituents of the C₁-C₆-aliphatic group representedby R⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

An eighth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, and provisos are each and independently asdescribed above in the seventh subset of variables of StructuralFormulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below

wherein each of rings A6, A8, A11, A14 and A15 is optionally andindependently further substituted. Suitable substituents are asdescribed above for ring A in the first subset of variables ofStructural Formulae XI(A) and XI(B).

Each R⁸ independently is halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl) or -N(C₁-C₄ alkyl)₂.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A ninth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of the group —[CR¹³R¹⁴]_(x)-ringA-Q²-R⁵, ring A, Q², R, R′, R⁶,R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n, including specific values, andprovisos are each and independently as described above in the eighthsubset of variables of Structural Formulae XI(A) and XI(B).

Each R⁵ is independently: i) —H; ii) an optionally substituted C₁-C₆alkyl group; iii) an optionally substituted, C₃-C₇ non-aromaticcarbocycle; or iv) an optionally substituted, 4-7 membered non-aromaticheterocycle, wherein said alkyl group represented by R⁵ is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, optionally substituted, C₃-C₇non-aromatic carbocycle, and optionally substituted, 4-7 memberednon-aromatic heterocycle. Each of said carbocycles and heterocyclesrepresented by R⁵, and referred to for the substituents of the C₁-C₆alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), NH₂, —NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl) and CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A tenth subset of variables of Structural Formulae XI(A) and XI(B) forthe compounds of the invention is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x and n,including specific values, and provisos are each and independently asdescribed above in the seventh subset of variables of StructuralFormulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below:

wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 isindependently and optionally further substituted. Suitable substituentsare as described above for ring A in the first subset of variables ofStructural Formulae XI(A) and XI(B).

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

An eleventh subset of variables of Structural Formulae XI(A) and XI(B)for the compounds of the invention is as follows:

Values of Q², R, R′, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, x, and n,including specific values, and provisos are each and independently asdescribed above in the seventh subset of variables of StructuralFormulae XI(A) and XI(B).

The group —[(C)₀₋₁R¹³R¹⁴]-ringA-Q²-R⁵ is independently selected from oneof the depicted below:

wherein each of rings A5-A7, A21, A24 and A26 is independently andoptionally further substituted. Suitable substituents are as describedabove for ring A in the first subset of variables of Structural FormulaeXI(A) and XI(B).

Each R⁸ independently is halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

Values of the remaining variables of Structural Formulae XI(A) andXI(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

In a twelfth subset of variables of Structural Formulae XI(A) and XI(B)for the compounds of the invention, values of the variables forStructural Formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the firstsubset of variables of Structural Formulae (IA) and (I).

In a thirteenth subset of variables of Structural Formulae XI(A) andXI(B)for the compounds of the invention, values of the variables forStructural Formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, oreleventh subset of variables of Structural Formulae XI(A) and XI(B); andwhere applicable:

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and provided thatif Q² is a bond, then R⁵ is an optionally substituted C₃-C₈ non-aromaticcarbocycle; an optionally substituted, 6-10-membered carbocyclic arylgroup; an optionally substituted, 4-8 membered non-aromatic heterocycle;or an optionally substituted, 5-10 membered heteroary group.

In a fourteenth subset of variables of Structural Formulae XI(A) andXI(B) for the compounds of the invention, values of the variables forStructural Formulae XI(A) and XI(B), including specific values, andprovisos are each and independently as described above in the thirteenthsubset of variables of Structural Formulae XI(A) and XI(B); and whereapplicable:

when Y¹ is a bond, the C₁-C₆ aliphatic group represented by R⁵ issubstituted with one or more instances of J^(C1), wherein J^(C1) isindependently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and—NRSO₂NR^(c)R^(b); or optionally two J^(C1) and two J^(D1),respectively, together with the atoms to which they are attached,independently form a 5-7-membered ring that is optionally substitutedwith one or more instances of J^(E1), and fused to the respective ringto which they are attached.

In a fifteenth subset of variables of Structural Formulae XI(A) andXI(B), values of the variables for Structural Formulae XI(A) and XI(B),including specific values, are each and independently as described abovein the thirteenth subset of variables of Structural Formulae (IA) and(I), in the eleventh subset of variables of Structural Formula (VI), orin the fifteenth subset of variables of Structural Formulae (II)-(V).

In another embodiment, the present invention generally relates tocompounds of Structural Formula XII(A) or XII(B), or pharmaceuticallyacceptable salts thereof.

A first subset of variables of Structural Formulae XII(A) and XII(B) forthe compounds of the invention is as follows:

Each Q³ is independently —C(O)—, —CO₂-, —C(O)NR′—, —SO₂-, —SO₂NR′—,—C(O)NRC(O)O—, or —(CR⁶R⁷)_(p)—Y¹—.

Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl,C₂-C₆ alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)(C₁-C₆-alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), and —CO₂R^(b); wherein each of said alkyl andalkenyl groups is optionally and independently substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy. Specifically, Ring B is optionally furthersubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, alkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl□,—CO₂H, and —CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, -NH₂,-NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, Ring B is optionally further substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, —NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂,C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl,C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy,CO₂H, and —CO₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or —CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R⁹ is —H or —CH₃.

R¹¹ and R¹² are each independently —H or —CH₃.

R¹³ and R¹⁴ are each independently —H or —CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each R and R′ is independently —H or C₁-C₆ alkyl.

Provided that if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group. Specifically, the C₁-C₆aliphatic group is substituted with one or more instances of J^(C1),wherein J^(C1) is independently selected from: an optionallysubstituted, C₃-C₈ non-aromatic carbocycle; an optionally substituted,6-10-membered carbocyclic aryl group; an optionally substituted, 4-8membered non-aromatic heterocycle; an optionally substituted, 5-10membered heteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a);NR^(b)R^(c); —C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b);—C(O)NR^(b)R^(c); —NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c);—C(O)NRCO₂R^(b); —NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b);—NRSO₂R^(b); and —NRSO₂NR^(c)R^(b); or optionally two J^(C1) and twoJ^(D1), respectively, together with the atoms to which they areattached, independently form a 5-7-membered ring that is optionallysubstituted with one or more instances of J^(E1), and fused to therespective ring to which they are attached.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A second subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention is as follows:

Values of Ring B, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, and R¹⁴,including specific values, and provisos are each and independently asdescribed above in the first subset of variables of Structural FormulaeXII(A) and XII(B).

Variable y=0 or 1.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A third subset of variables of Structural Formulae XII(A) and XII(B) isas follows:

Values of Ring B, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴ and y, includingspecific values, and provisos are each and independently as describedabove in the second subset of variables of Structural Formulae XII(A)and XII(B).

Q³ is independently —C(O)—, —CO₂-, —C(O)NH—, —C(O)N(CH₃)—,—C(O)NHC(O)O—, —C(O)N(CH₃)C(O)O—, —SO₂-, —SO₂NH—, —SO₂N(CH₃)—, or—(CR⁶R⁷)_(p)—Y¹—.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A fourth subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention is as follows:

Values of Ring B, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, and provisos are each and independently asdescribed above in the third subset of variables of Structural FormulaeXII(A) and XII(B).

R⁵ is independently i) —H; ii) a C₁-C₆ aliphatic group (e.g.,C₁-C₆-alkyl or C₂-C₆-alkenyl group) optionally substituted with one ormore instances ofJ^(C1); iii) a C₃-C₈ non-aromatic carbocycle optionallysubstituted with one or more instances of J^(C1); iv) a phenyl groupoptionally substituted with one or more instances of J^(C1); v) a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(C1); or vi) a 5-6 membered heteroaryl ringoptionally substituted with one or more instances of J^(D1).

Each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), -NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),—C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b).

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A fifth subset of variables of Structural Formulae XII(A) and XII(B)forthe compounds of the invention is as follows:

Values of Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, and provisos are each and independently asdescribed above in the fourth subset of variables of Structural FormulaeXII(A) and XII(B).

Ring B is optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl□, CO₂H, and —CO₂(C₁-C₄ alkyl),wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A sixth subset of variables of Structural Formulae XII(A) and XII(B) forthe compounds of the invention is as follows:

Values of Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, and provisos are each and independently asdescribed above in the fifth subset of variables of Structural FormulaeXII(A) and XII(B).

Ring B is independently selected from one of the structures depictedbelow:

wherein each of rings B1, B2 and B4-B9 is optionally and independentlysubstituted. Suitable substituents are independently as described abovefor ring B in the first subset of variables of Structural Formulae (IA)and (I).

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A seventh subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention is as follows:

Values of the ring B, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, x andy, including specific values, and provisos are each and independently asdescribed above in the sixth subset of variables of Structural FormulaeXII(A) and XII(B).

Each R⁵ is independently: i) —H; ii) a C₁-C₆-aliphatic group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —CO₂H, —C₃-C₈non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle,and 5-6 membered heteroaryl; or iii) a C₃-C₇ non-aromatic carbocycle, a4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 memberedheteroaryl ring, each of which is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), NH₂, —NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), and —CO₂H; whereineach of said alkyl groups for the substituents of the aliphatic group,carbocycle, heterocycle, phenyl and heteroaryl group represented by R⁵is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, andheteroaryl for the substituents of the C₁-C₆—aliphatic group representedby R⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

An eighth subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention is as follows:

, Values Q³, R, R′, R⁵, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y, includingspecific values, and provisos are each and independently as describedabove in the seventh subset of variables of Structural Formulae XII(A)and XII(B).

The group —[C(R¹³R¹⁴)]_(x)-ringB-Q²-R⁵:

wherein ring B2 is optionally and independently further substituted withone or more substituents independently selected from the groupconsisting of with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₂alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy,C₁-C₂ haloalkoxy, C₂ -C₄ alkoxyalkoxy, CO₂H, and —CO₂(C₁-C₄ alkyl).

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

A ninth subset of variables of Structural Formulae XII(A) and XII(B) forthe compounds of the invention is as follows:

Values of ring B, Q³, R, R′, R⁶, R⁷, R⁹, R¹¹, R¹², R¹³, R¹⁴, and y,including specific values, and provisos are each and independently asdescribed above in the eighth subset of variables of Structural FormulaeXII(A) and XII(B).

Each R⁵ is independently: i) —H; ii) an optionally substituted C₁-C₆alkyl group; iii) an optionally substituted, C₃-C₇ non-aromaticcarbocycle; or iv) an optionally substituted, 4-7 membered non-aromaticheterocycle, wherein said alkyl group represented by R⁵ is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), —C₁-C₄ alkoxy, optionally substituted, C₃-C₇non-aromatic carbocycle, and optionally substituted, 4-7 memberednon-aromatic heterocycle. Each of said carbocycles and heterocyclesrepresented by R⁵, and referred to for the substituents of the C₁-C₆alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, —NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formulae XII(A) andXII(B), including specific values, and provisos are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

In a tenth set of variables of Structural Formulae XII(A) and XII(B) forthe compounds of the invention, values of the variables for StructuralFormulae XII(A) and XII(B), including specific values, and provisos areeach and independently as described above in the first subset ofvariables of Structural Formulae (IA) and (I).

In an eleventh subset of variables of Structural Formulae XII(A) andXII(B)for the compounds of the invention, values of the variables forStructural Formulae XII(A) and XII(B), including specific values, andprovisos are each and independently as described above in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, oreleventh subset of variables of Structural Formulae XII(A) and XII(B);and where applicable:

provided that if Y¹ is a bond, then R⁵ is a substituted C₁-C₆ aliphaticgroup; an optionally substituted C₃-C₈ non-aromatic carbocycle; anoptionally substituted, 6-10-membered carbocyclic aryl group; anoptionally substituted, 4-8 membered non-aromatic heterocycle; or anoptionally substituted, 5-10 membered heteroary group; and

provided that if Q³ is a bond, then R⁵ is an optionally substitutedC₃-C₈ non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; or an optionally substituted, 5-10 memberedheteroary group.

In a twelfth subset of variables of Structural Formulae XII(A) andXII(B)for the compounds of the invention, values of the variables forStructural Formulae XII(A) and XII(B), including specific values, andprovisos are each and independently as described above in the eleventhsubset of variables of Structural Formulae XII(A) and XII(B); and whereapplicable:

when Y¹ is a bond, the C₁-C₆ aliphatic group represented by R⁵ issubstituted with one or more instances of J^(C1), wherein J^(C1) isindependently selected from: an optionally substituted, C₃-C₈non-aromatic carbocycle; an optionally substituted, 6-10-memberedcarbocyclic aryl group; an optionally substituted, 4-8 memberednon-aromatic heterocycle; an optionally substituted, 5-10 memberedheteroaryl group; —OR^(b); —SR^(b); —S(O)R^(a); —SO₂R^(a); —NR^(b)R^(c);—C(O)R^(b); —C(O)OR^(b); —OC(O)R^(b); —NRC(O)R^(b); —C(O)NR^(b)R^(c);—NRC(O)NR^(b)R^(c); —NRC(O)OR^(b); —OCONR^(b)R^(c); —C(O)NRCO₂R^(b);—NRC(O)NRCO₂R^(b); —C(O)NR(OR^(b)); —SO₂NR^(c)R^(b); —NRSO₂R^(b); and—NRSO₂NR^(c)R^(b); or optionally two J^(C1) and two J^(D1),respectively, together with the atoms to which they are attached,independently form a 5-7-membered ring that is optionally substitutedwith one or more instances of J^(E1), and fused to the respective ringto which they are attached.

In a thirteenth subset of variables of Structural Formulae XII(A) andXII(B), values of the variables for Structural Formulae XII(A) andXII(B), including specific values, are each and independently asdescribed above in the thirteenth subset of variables of StructuralFormulae (IA) and (I), in the eleventh subset of variables of StructuralFormula VI, or in the fifteenth subset of variables of StructuralFormulae II-V.

In another embodiment, the present invention generally relates tocompounds of Structural Formula XIII, or pharmaceutically acceptablesalts thereof:

A first subset of variables of Structural Formula XIII for the compoundsof the invention is as follows:

Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, C₂-C₆alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)(C₁-C₆-alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), and —CO₂R^(b); wherein each of said alkyl andalkenyl groups is optionally and independently substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy. Specifically, ring C is optionally further substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), CO₂H and —CO₂(C₁-C₄alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, ring Cis optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, -NH₂, -NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, CO₂H, and—CO₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or —CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R⁹ is —H or —CH₃.

R¹¹ and R¹² are each independently —H or —CH₃.

Each R and R′ is independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first subset of variables of Structural Formulae (IA) and(I).

A second subset of variables of Structural Formula XIII for thecompounds of the invention is as follows:

Values of Ring C, R, R′, R⁶, R⁷, R⁹, R¹¹, and R¹², including specificvalues, are each and independently as described above in the firstsubset of variables of Structural Formula XIII.

R¹⁰ is —H or C₁-C₆-alkyl.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first subset of variables of Structural Formulae (IA) and(I).

A third subset of variables of Structural Formula XIII for the compoundsof the invention is as follows:

Values of R, R′, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹², including specificvalues, are each and independently as described above in the secondsubset of variables of Structure Formula XIII.

Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionallyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, hydroxy, C₁-C₄ alkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl),—CO₂H, and —CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first subset of variables of Structural Formulae (IA) and(I).

A fourth subset of variables of Structural Formula XIII for thecompounds of the invention is as follows:

Values of R, R′, R⁶, R⁷, R⁹, R¹¹, R¹⁰, R¹¹, and R¹², including specificvalues, are each and independently as described above in the thirdsubset of variables of Structure Formula XIII.

Ring C is independently selected from:

wherein each of rings C₁-C5 is optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, C₁-C₄ alkyl, —O(C₁-C₄ alkyl),-NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —CO₂H, and—CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more independently substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Specifically, each of rings C₁-C5 is optionally and independentlyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, -NH₂, -NH(C₁-C₂alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy,C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, —CO₂H, and —CO₂(C₁-C₄ alkyl).

Values of the remaining variables of Structural Formula XIII, includingspecific values, and provisos are each and independently as describedabove in the first subset of variables of Structural Formulae (IA) and(I).

In a fifth set of variables of Structural Formula XIII for the compoundsof the invention, values of the variables for Structural Formula XIII,including specific values, are each and independently as described abovein the first subset of variables of Structural Formulae (IA) and (I).

In another embodiment, the present invention generally relates tocompounds represented by Structural Formula below XIV, or apharmaceutically acceptable salt thereof:

(XIV).

A first subset of variables of Structural Formula XIV for the compoundsof the invention is as follows:

Ring D is 4-7 membered, non-aromatic, heterocyclic ring optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and —CO₂R^(b); wherein each of said alkyl and alkenyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, ring D is optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C 4 alkyl), —CO₂H and—CO₂(C 1-C₄ alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Specifically, ring Dis optionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl,C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy,C₁-C₂ hydroxyalkoxy, C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, —CO₂H, and—CP₂(C₁-C₄ alkyl).

R⁶ and R⁷ are each independently —H or —CH₃, or together with the carbonatoms to which they are attached they form a cyclopropane ring.

R¹³ and R¹⁴ are each independently —H or —CH₃, or together with thecarbon atoms to which they are attached they form a cyclopropane ring.

Each of R and R′ is independently —H or C₁-C₆ alkyl.

Values of the remaining variables of Structural Formula XIV, includingspecific values, and provisos are each and independently as describedabove in the first subset of variables of Structural Formulae (IA) and(I).

A second subset of variables of Structural Formula XIV for the compoundsof the invention is as follows:

Values for Ring D, R, R′, R⁶, R⁷, R¹³, and R¹⁴, including specificvalues, are each and independently as described above in the firstsubset of variables of Structural Formula XIV.

Variable z is 1.

All other variables of Structural Formula XIV, including specificvalues, and provisos are each and independently as described above forthe first subset of variables of Structural Formulae (IA) and (I).

A third subset of variables of Structural Formula IV for the compoundsof the invention is as follows:

Values for z, R, R′, R⁶, R⁷, R¹³, and R¹⁴, including specific values,are each and independently as described above in the second subset ofvariables of Structural Formula XIV.

Ring D is independently selected from the group consisting of

wherein each of rings D1-D7 is optionally and independently substitutedone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl),—CO₂H and —CO₂(C₁-C₄ alkyl), wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

Specifically, each of rings D1-D7 is optionally and independentlyfurther substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₂ alkyl), -NH(C₁-C₂ alkyl)₂, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂hydroxyalkyl, C₂-C₄ alkoxyalkyl, C₁-C₂ alkoxy, C₁-C₂ hydroxyalkoxy,C₁-C₂ haloalkoxy, C₂-C₄ alkoxyalkoxy, —CO₂H, and —CO₂(C₁-C₄ alkyl).

Each R^(d) is independently —H, C₁-C₆ alkyl or —C(O)(C₁-C₆ alkyl),wherein each of said alkyl moiety is optionally and independentlysubstituted with one or more groups selected from halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, each R^(d) is independently —H or C₁-C₆ alkyl optionallyand independently substituted with one or more groups selected fromhalogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

Values of the remaining variables of Structural Formula XIV, includingspecific values, and provisos are each and independently as describedabove for the first subset of variables of Structural Formulae (IA) and(I).

In a fourth subset of variables of Structural Formula XIV for thecompounds of the invention, values of the variables for StructuralFormula XIV, including specific values and provisos, are each andindependently as described above in the first subset of variables ofStructural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralStructural Formula (I), or pharmaceutically acceptable salts thereof,wheren each variables of the formulae are independently as describedabove; and wherein:

R⁴ is:

Ring E is a C₄-C₈ non-aromatic carbocycle optionally further substitutedwith one or more instances of J^(A).

Rings F is a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1).

Each of rings G1 and G2 is independently a 5-10 membered non-aromaticbridged carbocycle optionally substituted with one or more instances ofJ^(A).

Q² is independently bond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂-,—OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—,—NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—.

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; or iv) anoptionally substituted, 4-7 membered non-aromatic heterocycle; oroptionally, together with R and the nitrogen atom to which it isattached, form a 5-7 membered, optionally substituted non-aromaticheterocycle. The alkyl group represented by R⁵ is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), C₁-C₄ alkoxy, an optionally substituted, C₃-C₇ non-aromaticcarbocycle, and an optionally substituted, 4-7 membered non-aromaticheterocycle; wherein each of said carbocycles and heterocyclesrepresented by R⁵, and referred to for the substituents of the C₁-C₆alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

Each of R⁸ and R⁹ is independently —H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C ₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R¹¹, R¹², R¹³ and R¹⁴ are each independently —H, halogen, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or optionally,R¹³ and R¹⁴, together with the carbon atom to which they are attached,form a cyclopropane ring, optionally substituted with one or moreinstances of methyl.

R²¹, R²², R²³ and R²⁴ are each independently —H, halogen, —OH, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

Values of the remaining variables of Structural formula I, includingspecific values, and provisos are each and independently as describedabove in any one of the first through fifteenth sets of variables ofStructural Formula I.

In yet another embodiment, the compounds represented by StructuralFormula (I) or pharmaceutically acceptable salts thereof areindependently as described above in the preceding paragraph; and ring Fis selected from any one of rings F1-F6:

each of rings F1-F6 optionally and independently substituted; and

each R^(f) is independently —H or C₁-C₆ alkyl optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy and C₂-C₆ alkoxyalkoxy.

In yet another embodiment, the compounds represented by StructuralFormula (XIA) or (XIB), or pharmaceutically acceptable salts thereof areas described above; and

the group —[C(R¹³R¹⁴)]_(x)-ringA-Q²-R⁵ is independently:

wherein:

each of rings A14 and A28 is optionally and independently furthersubstituted; and values of the remaining variables of StructuralFormulae (XIA) and (XIB), including specific values, and provisos areeach and independently as described above in any one of the firstthrough eleventh sets of variables of Structural Formulae (XIA) and(XIB).

In yet another embodiment, the compounds represented by StructuralFormula (XIA) or (XIB), or pharmaceutically acceptable salts thereof areindependently as described above in the preceding paragraph; and R⁵ isan optionally substituted C₁-C₆ alkyl group; an optionally substituted,C₃-C₇ non-aromatic carbocycle; or an optionally substituted, 4-7membered non-aromatic heterocycle; or optionally, together with R andthe nitrogen atom to which it is attached, form a 5-7 membered,optionally substituted non-aromatic heterocycle. Specifically, R⁵ is anoptionally substituted, 4-7 membered non-aromatic heterocycle; oroptionally, together with R and the nitrogen atom to which it isattached, form a 5-7 membered, optionally substituted non-aromaticheterocycle.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Ring E is a C₄-C₁₀ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A).

Rings F is a 4-8 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J″. Specific examples of ringF includes:

Additional example includes

Each of rings F1-F7 optionally and independently substituted. Exemplarysubstituents for ring F (including rings F1-F7) include halogen, cyano,hydroxy, C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with oneor more substituents selected from the group consisting of halogen,cyano, hydroxy, and —O(C₁-C₄ alkyl).

R^(f) is independently —H or C₁-C₆ alkyl optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy and C₂-C₆ alkoxyalkoxy.

R⁹ is independently —H, halogen, cyano, hydroxy, amino, carboxy, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,or C₂-C₆ alkoxyalkoxy.

R¹¹, R¹², R¹³ and R¹⁴ are each independently —H, halogen, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

Optionally, R¹³ and R¹⁴, together with the carbon atom to which they areattached, form a cyclopropane ring, optionally substituted with one ormore instances of methyl.

s is 0, 1 or 2.

x is 0, 1 or 2.

The remaining variables are each and independently as described above inany one of the sets of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (I) or (IA), or pharmaceutically acceptable salts thereof,wherein:

Ring E is a C₄-C₈ non-aromatic carbocycle optionally further substitutedwith one or more instances of J^(A).

R⁹ is independently —H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

The other varibales are each and independently as described in thepreceeding paragraph.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Each of rings G1-G4 is independently a 5-10 membered non-aromaticbridged ring optionally further substituted with one or more instancesof J^(A).

Eing G5 is a 5-10 membered non-aromatic bridged ring optionally furthersubstituted with one or more instances of J^(B).

X is —O—, —S—, or —NR^(g)—.

R⁸ and R⁹ are each independently —H, halogen, cyano, hydroxy, amino,carboxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cyanoalkyl, C₂-C₆alkoxyalkyl, C₁-C₆ aminoalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ carboxyalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy, or C₂-C₆ alkoxyalkoxy.

R¹³ and R¹⁴ are each independently —H, halogen, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

Optionally, R¹³ and R¹⁴, together with the carbon atom to which they areattached, form a cyclopropane ring, optionally substituted with one ormore instances of methyl.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —H, halogen, —OH,C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy. Specifically, R²¹, R²², R²³, R²⁴, and R²⁵ areeach independently —H, halogen, —OH, C₁-C₆ alkoxy, or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, C₁-C₆alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,—C(O)(C₁-C₆—alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl).

R^(g) is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy.

q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

The remaining variables are each and independently as described above inany set of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), pharmaceutically acceptable salts thereof, wherein:

R⁴ is:

wherein rings G1 and G2 are each and independently a 5-10 memberednon-aromatic bridged ring optionally further substituted with one ormore instances of J^(A).

Each of R⁸ and R⁹ is independently -—H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or N(C₁-C₄ alkyl)₂.

R²¹, R²², R²³, and R²⁴ are each independently —H, halogen, —OH, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, oxo, hydroxy, oxo,amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy.

Q² is independently a bond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂-,—OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—,—NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—. Alternatively Q² is independently —O—, —CO₂-, —OC(O)—,—C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-, —OC(O)NR—, —CO₂SO₂-, —P(O)₂O—,or —(CR⁶R⁷)_(p)—Y¹—.

Alternatively Q² is independently —O—or CO₂-.

In some embodiments, rings E and G (including G1-G5) are optionally andindependently further substituted with one or more instances of J^(A)(for carbocycle) or J^(B) (for heterocycle), wherein each of J^(A) andJ^(B) is independently selected from the group consisting of halogen,cyano, oxo, -NCO, and Q¹-R⁵, and wherein:

Q¹ is independently a bond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂-,—OC(O)—, —C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—,—NRCO₂-, —OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—, and Y¹ is independently a bond, —O—, —S—, —NR′—,—C(O)—, —C(═NR)—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —S(O)—,—SO₂-, —SO₂NR′—, —NRSO₂-, or —NRSO₂NR′—. Alternatively: Q¹ isindependently a bond, —O—, —S—, —NR—, —C(O)—, —CO₂-, —OC(O)—, —C(O)NR—,—C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—; and Y¹ is independently —O—, —CO₂-, —OC(O)—, —C(O)NR—,—NRC(O)—, —NRC(O)NR—, —NRCO₂-, or —OC(O)NR—.

In yet another embodiment, Q¹ and Y¹ are each independently as describedabove in the preceeding paragraph, and:

R⁵ is independently i) —H; ii) a C₁-C₆-aliphatic group optionallysubstituted with one or more instances of J^(C1); iii) a C₃-C₈non-aromatic carbocycle optionally substituted with one or moreinstances of J^(C1); iv) a phenyl group optionally substituted with oneor more instances of J^(C1); v) a 4-8 membered non-aromatic heterocycleoptionally substituted with one or more instances of J^(D1) or vi) a 5-6membered heteroaryl ring optionally substituted with one or moreinstances of J^(D1); and

each of J^(C1) and J^(D1) is independently selected from the groupconsisting of halogen, cyano, oxo, R^(a), —OR^(b), —SR^(b), —S(O)R^(a),—SO₂R^(a), -NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b), —NHC(O)R^(b),—C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), -NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b).

In some specific embodiments, the compounds are represented byStructural Formula (IA) or (I), wherein:

R¹ is —H.

R² is —H, —CH₃, —CH₂OH, or -NH₂. Specifically, R² is —H, or —CH₂OH.

R³ is —H, —F, —Cl, C₁₋₄ alkyl, or C₁₋₄ haloalkyl. Alternatively, R³ is—H, —F, or —Cl.

Z¹ is —H, —F, or —Cl.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Z³ is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; iv) an optionallysubstituted, 4-7 membered non- aromatic heterocycle; v))an optionallysubstituted phenyl group; vi) an optionally substituted 5-6 memberedheteroaryl ring; or optionally, together with R and the nitrogen atom towhich it is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle; and said alkyl group represented by R⁵ isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,-NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, —NRCO(C₁-C₄ alkyl), —CONR(C₁-C₄alkyl), —NRCO₂(C₁-C₄ alkyl), a C₃-C₇ non-aromatic carbocycle optionallysubstituted with one or more instances of J^(E1), a 4-7 memberednon-aromatic heterocycle optionally substituted with one or moreinstances of J^(E1); and a phenyl optionally substituted with one ormore instances of J^(E1); and

wherein each of said carbocycle, heterocycle, phenyl and heteroaryrepresented by R⁵ is independently and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

The remaining variables, including R⁴ that includes a spiro ringrepresented by rings E and F, or a bridged ring represented by ringsG1-G5, are each and independently as described in any one of thepreceeing four embodiments.

In yet another embodiment, the compounds are presented by StructuralFormula (IA) or (I), wherein values of the variabels are each andindependently as described in the preceeding embodiment, except:

Z² is —H;

Z³ is —H;

R⁵ is independently: i) —H or ii) a C₁-C₆-alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —CO₂H, C₃-C₈non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl,and 5-6 membered heteroaryl;

wherein each of said alkyl groups referred to in the substituents of theC₁-C₆-alkyl group represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; and

wherein each of said carbocycle, phenyl, heterocycle, and heteroarylreferred to in the substituents of the C₁-C₆-alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, -NH₂,-NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.

In yet another embodiment, each of rings E, G1-G5 is independently andoptionally substituted with onr or more substituents selected from thegroup consisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆-alkyl),—OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), and —CO₂R^(b); wherein each of said alkyl groups is optionallyand independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.Specifically, each of rings E, G1-G5 is independently and optionallysubstituted with onr or more substituents selected from the groupconsisting of halogen, cyano, hydroxy, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ —CO(C₁-C 4 alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, and C₁-C₄ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁-C₄ alkyl).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts thereof,wherein:

R⁴ is:

Ring A is a non-aromatic, 5-10 membered, bridged carbocylce orheterocycle, or ring A and R⁸ optionally form a non-aromatic, 5-10membered, bridged carbocycle or heterocycle, or ring A and R⁹ optionallyform a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle,or ring A and R¹¹ optionally form a non-aromatic, 5-10 membered, bridgedcarbocycle or heterocycle, wherein each of said carbocycle isindependently and optionally substituted with one or more instances ofJ^(A) and wherein each carbocycle is independently and optionallysubstituted with one or more instances of J^(B).

R¹ is —H.

R² is —H, CH₃, —CH₂OH, or -NH₂. Specifically, R² is —H, or —CH₂OH.

R³ is —H, —F, —Cl, C₁₋₄ alkyl (e.g., —CH₃ or —C₂H₅), or C₁₋₄ haloalkyl(e.g., —CF3).

Alternatively, R³ is —H, —F, or —Cl.

Z¹ is —H, —F, or —Cl.

Z² is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Z³ is —H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl).

Q² is independently —O—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—,—NRC(O)—, —NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —P(O)(OR)O—,—OP(O)(OR^(a))O—, —P(O)₂O—, —CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—.

Y¹ is —O—, —CO₂-, —OC(O)—, —C(O)NR′—, —C(O)NRC(O)O—, —NRC(O)—,—NRC(O)NR′—, —NRCO₂-, —OC(O)NR′—, —P(O)(OR)O—, —OP(O)(OR^(a))O—,—P(O)₂O—, or —CO₂SO₂-.

R⁵ is: i) —H; ii) an optionally substituted C₁-C₆ alkyl group; iii) anoptionally substituted, C₃-C₇ non-aromatic carbocycle; iv) an optionallysubstituted, 4-7 membered non-aromatic heterocycle; v))an optionallysubstituted phenyl group; vi) an optionally substituted 5-6 memberedheteroaryl ring; or optionally, together with R and the nitrogen atom towhich it is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle; and

said alkyl group represented by R⁵ is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, —NRCO(C₁-C₄ alkyl), —CONR(C₁-C₄ alkyl), —NRCO₂(C₁-C₄ alkyl), aC₃-C₇ non-aromatic carbocycle optionally substituted with one or moreinstances of J^(E1), a 4-7 membered non-aromatic heterocycle optionallysubstituted with one or more instances of J^(E1); and a phenyloptionally substituted with one or more instances of J^(E1);

wherein each of said carbocycle, heterocycle, phenyl and heteroaryrepresented by R⁵ is independently and optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.

Each of R⁸ and R⁹ is independently —H, halogen, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄alkyl), -NH₂, -NH(C₁-C₄ alkyl), or -N(C₁-C₄ alkyl)₂.

R¹¹, R¹², R¹³, and R¹⁴ are each independently —H, halogen, or C₁-C₆alkyl optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, and C₁-C₆alkoxy.

Each of J^(A) and J^(B) is independently selected from the groupconsisting of halogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, —C(O)(C₁-C₆—alkyl), —OC(O)(C₁-C₆ alkyl),—NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), and —CO₂R^(b);wherein each of said alkyl groups is optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

n is 0 or 1.

x is 0 or 1.

The remaining variables are each and independently as described above inany set of variables for Structural Formulae (IA) and (I).

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts, wherein:

R⁴ is:

Each of rings G1-G4 is independently a 5-10 membered non-aromaticbridged carbocycle optionally further substituted with one or moreinstances of J^(A), and ring G5 is a 5-10 membered non-aromatic bridgedheterocycle optionally further substituted with one or more instances ofJ^(B).

X is —O—, —S—, or —NR^(g)—.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —H, halogen, —O—H,C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁-C₆ alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆alkyl)₂, —O(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)(C₁-C₆—alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),-N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl).

R^(g) is -H or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, oxo, hydroxy, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy.

q is 0, 1 or 2.

r is 1 or 2.

The remaining variables are each and independently as described above inthe preceeding paragraph.

In yet another embodiment, the compounds are represented by StructuralFormula (IA) or (I), or pharmaceutically acceptable salts thereof,wherein the variables are each and independently as described above inthe preceeding paragraph except those described below:

R¹ is —H.

R² is —H.

R³ is —H, —F, —Cl, C₁-4 alkyl, or C₁-4 haloalkyl. Alternatively, R³ is—H, —F, or —Cl.

Z¹ is ——H, —F, or —Cl.

Z² is —H.

Z³ is —H.

X is —O—.

R⁵ is —H, an optionally substituted C₁-C₆ alkyl, or optionallysubstituted phenyl.

Each R⁸ is independently -—H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —O(C₁-C₄ alkyl).

Each of R⁹, R¹³, and R¹⁴ is independently —H or C₁-C₄ alkyl.

R²¹, R²², R²³, R²⁴, and R²⁵ are each independently —H, halogen, —OH,C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆ alkyl, and —O(C₁-C₆ alkyl). Specifically R²¹,R²², R²³, R²⁴, and R²⁵ are each independently —H, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

Each rings G1-G5 are independently and optionally substituted with oneor more substituents selected from the group consisting of halogen,cyano, hydroxy, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆alkyl), C₁-C₄ alkyl that is optionally substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy, andC₁-C₄ alkoxy.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-VI (hereinafter reference to Structural FormulaeI-VI includes Structural Formulae I, IA, II, III, IV, V, VI) andXI(A)-XIV (hereinafter reference to Structural Formulae XI(A)-XIVincludes Structural Formulae XIA, XIB, XIIA, XIIB, XIII, and XIV),wherein values of the variables therein are independently as describedabove in any embodiments for the compounds of the invention, except thatR³ is C₁₋₆ alkyl, such as methyl or ethyl.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-VI and XI(A)-XIV, wherein values of the variablestherein are independently as described above in any embodiments for thecompounds of the invention, except that x is 0.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values ofthe variables therein are independently as described above in anyembodiments for the compounds of the invention, except that ring A isbridged.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I, IA, II, VI, XI(A), and XI(B), wherein values ofthe variables therein are independently as described above in anyembodiments for the compounds of the invention, except that Q² isindependently —C(═NR)—, —C(═NR)NR—, —NRC(═NR)NR—, —CO₂-, —OC(O)—,—C(O)NR—, —C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, —P(O)(OR)O—,—OP(O)(OR^(a))O—, —P(O)₂O—, —CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—, oralternatively, Q² is independently —CO₂-, —OC(O)—, —C(O)NR—,—C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂-,—OC(O)NR—, —S(O)—, —SO₂-, -N(R)SO₂-, —SO₂N(R)-, —NRSO₂NR—, —P(O)(OR)O—,—OP(O)(OR^(a))O—, —P(O)₂O—, —CO₂SO₂-, or —(CR⁶R⁷)_(p)—Y¹—.

In yet another embodiment, the compounds are represented by any one ofStructural Formulae I-VI and XI(A)-XIV, wherein values of the variablestherein are independently as described above in any embodiments for thecompounds of the invention, provided that when Q² is —O—or —NR—, thenring A is further substituted with J^(A) other than —H; and providedthat if Q³ is —C(O)—, then R⁵ is a substituted C₁-C₆ aliphatic group; anoptionally substituted C₃-C₈ non-aromatic carbocycle; an optionallysubstituted, 6-10-membered carbocyclic aryl group; optionallysubstituted, 4-8 membered non-aromatic heterocycle; or an optionallysubstituted 5-10 membered heteroaryl group. In a specific embodiment,when Q² is —O—or —NR—, then ring A is further substituted with J^(A)other than —H at the geminal position to -Q²R⁵.

In yet another embodiment, the present invention is directed to any oneof the compounds depicted in FIGS. 3-5, or pharmaceutically acceptablesalts thereof.

In yet another embodiment, the present invention is directed to any oneof the compounds depicted in FIG. 6, or pharmaceutically acceptablesalts thereof In yet another embodiment, the present invention isdirected to any one of the compounds depicted in FIG. 7, orpharmaceutically acceptable salts thereof. In yet another embodiment,the present invention is directed to any one of the compounds depictedin FIG. 8, or pharmaceutically acceptable salts thereof.

In some embodiments, the variables of Structural Formulae I-VI andXI(A)-XIV are each and independently as depicted in the compounds ofFIGS. 3-8.

Each and independently as described above for the methods of theinvention, the aforementioned compounds of the invention can be usefulas inhibitors of influenza virus replication in biological samples or ina patient. These compounds can also be useful in reducing the amount ofinfluenza viruses (viral titer) in a biological sample or in a patient.They can also be useful for therapeutic and prophylactic treatment ofinfections caused by the influenza viruses in a biological sample or ina patient.

The present invention also provides methods of preparing a compound ofthe invention. In one embodiment, the methods are directed to preparecompounds represented by Structural Formula (IA) or pharmaceuticallyacceptable salts thereof. The methods comprise a step of reactingreacting compound A:

with compound B:

to form a compound represented by Structural Formula (XX), as shown inScheme A below:

The variables of Structural Formulae (IA) and (XX), and compounds (A)and (B) are independently as defined in any one of the embodimentsdescribed above. Ts is tosyl. Any suitable reaction condition known inthe art, for example, in WO 2005/095400 and WO 2007/084557 for thecoupling of a dioxaboraolan with a chloro-pyrimidine can be employed forthe reaction between compound (A) and (B). For example, the reactionbetween compound (A) and (B) can be performed in the presence ofPd(PPh₃)₄. Specific exemplary conditions are described in theExemplification below (e.g., General Schemes 5A, 6A, 7, 11, 14, 16, 31,32, 33, 40, 44, 49, 51, 52, 58, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70,76).

In another embodiment, the methods comprise a step of reacting reactingcompound C1 or C₂ with NH₂R⁴ to form a compound represented byStructural Formula (XX), as shown in Scheme B below:

The variables of Structural Formulae (IA) and (XX), compounds (C1) and(C₂), and R⁴ of NH₂R⁴ are independently as defined in any one of theembodiments described above. Ts is tosyl. Any suitable reactioncondition known in the art, for example, in WO 2005/095400 and WO2007/084557 for the coupling of an amine with a sulfinyl group can beemployed for the reaction of compounds (C1) and (C2) with NH₂R⁴.Specific exemplary conditions are described in the Exemplification below(e.g., General Schemes 13,15, 19, 20, 23, 30, 39, 41, 42, 44, 45, 50,53, 54, 65, 72, 73, 74, and 77).

The methods described above with reference to Schemes A and B optionallyand independently further comprises deprotecting the Ts group of thecompound of Structural Formula (XX) to form the compound of StructuralFormula (IA). Any suitable condition for deprotecting a Ts group knownin the art can be employed in the invention. Specific exemplaryconditions are described in the Exemplification below. The de-tosylationcan generate the compounds of Structural Formula (IA) where R¹ is —H. Ifdesired, the R¹ position can be alkylated by any suitable method knownin the art to from the compounds of Structural Formula (IA) where R¹ isC₁₋₆ alkyl.

Compounds (A), (B), (C₁), (C₂), and NH₂R⁴ can be prepared by anysuitable method known in the art. Specific exemplary synthethic methodsare described below in the Exemplification below. For example, compound(C1) can be prepared as described in Scheme C: reaction betweencompounds (D) and (E), for example, in the presence of Pd(PPh₃)₄ canproduce compound (F). Compound (F) can then be oxidated under suitableconditions, for example, by treatment with meta-chloroperbenzoic acid toform compound (C). (See, for example, detailed experimental detailsdescribed in the Exemplification for General Scheme 44.)

Definitions and General Terminology

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausolito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as illustrated generallybelow, or as exemplified by particular classes, subclasses, and speciesof the invention. It will be appreciated that the phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted.” In general, the term “substituted”, whether preceded bythe term “optionally” or not, refers to the replacement of one or morehydrogen radicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position. When the term“optionally substituted” precedes a list, said term refers to all of thesubsequent substitutable groups in that list. If a substituent radicalor structure is not identified or defined as “optionally substituted”,the substituent radical or structure is unsubstituted. For example, if Xis optionally substituted C₁-C₃alkyl or phenyl; X may be eitheroptionally substituted C₁-C₃ alkyl or optionally substituted phenyl.Likewise, if the term “optionally substituted” follows a list, said termalso refers to all of the substitutable groups in the prior list unlessotherwise indicated. For example: if X is C₁-C₃alkyl or phenyl wherein Xis optionally and independently substituted by J^(X), then bothC₁-C₃alkyl and phenyl may be optionally substituted by J^(X). As isapparent to one having ordinary skill in the art, groups such as —H,halogen, NO₂, CN, NH₂,OH, or OCF₃ would not be substitutable groups.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3. As described herein, aspecified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

Selection of substituents and combinations of substituents envisioned bythis invention are those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, specifically,their recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week. Only those choicesand combinations of substituents that result in a stable structure arecontemplated. Such choices and combinations will be apparent to those ofordinary skill in the art and may be determined without undueexperimentation.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), or branched, hydrocarbon chain thatis completely saturated or that contains one or more units ofunsaturation but is non-aromatic. Unless otherwise specified, aliphaticgroups contain 1-20 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-10 aliphatic carbon atoms. In otherembodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. Instill other embodiments, aliphatic groups contain 1-6 aliphatic carbonatoms, and in yet other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms. Aliphatic groups may be linear or branched,substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specificexamples include, but are not limited to, methyl, ethyl, isopropyl,n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl andacetylene.

The term “alkyl” as used herein means a saturated straight or branchedchain hydrocarbon. The term “alkenyl” as used herein means a straight orbranched chain hydrocarbon comprising one or more double bonds. The term“alkynyl” as used herein means a straight or branched chain hydrocarboncomprising one or more triple bonds. Each of the “alkyl”, “alkenyl” or“alkynyl” as used herein can be optionally substituted as set forthbelow. In some embodiments, the “alkyl” is C₁-C₆ alkyl or C₁-C₄ alkyl.In some embodiments, the “alkenyl” is C₂-C₆ alkenyl or C₂-C₄ alkenyl. Insome embodiments, the “alkynyl” is C₂-C₆ alkynyl or C₂-C₄ alkynyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“carbocyclic”) refers to a non-aromatic carbon only containing ringsystem which can be saturated or contains one or more units ofunsaturation, having three to fourteen ring carbon atoms. In someembodiments, the number of carbon atoms is 3 to 10. In otherembodiments, the number of carbon atoms is 4 to 7. In yet otherembodiments, the number of carbon atoms is 5 or 6. The term includesmonocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclicring systems. The term also includes polycyclic ring systems in whichthe carbocyclic ring can be “fused” to one or more non-aromaticcarbocyclic or heterocyclic rings or one or more aromatic rings orcombination thereof, wherein the radical or point of attachment is onthe carbocyclic ring. “Fused” bicyclic ring systems comprise two ringswhich share two adjoining ring atoms. Bridged bicyclic group comprisetwo rings which share three or four adjacent ring atoms. Spiro bicyclicring systems share one ring atom. Examples of cycloaliphatic groupsinclude, but are not limited to, cycloalkyl and cycloalkenyl groups.Specific examples include, but are not limited to, cyclohexyl,cyclopropenyl, and cyclobutyl.

The term “heterocycle” (or “heterocyclyl”, or “heterocyclic” or“non-aromatic heterocycle”) as used herein refers to a non-aromatic ringsystem which can be saturated or contain one or more units ofunsaturation, having three to fourteen ring atoms in which one or morering carbons is replaced by a heteroatom such as, N, S, or O and eachring in the system contains 3 to 7 members. In some embodiments,non-aromatic heterocyclic rings comprise up to three heteroatomsselected from N, S and O within the ring. In other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N, S and O within the ring system. In yet other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N and O within the ring system. The term includes monocyclic,bicyclic or polycyclic fused, spiro or bridged heterocyclic ringsystems. The term also includes polycyclic ring systems in which theheterocyclic ring can be fused to one or more non-aromatic carbocyclicor heterocyclic rings or one or more aromatic rings or combinationthereof, wherein the radical or point of attachment is on theheterocyclic ring. Examples of heterocycles include, but are not limitedto, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl,triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl,benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, forexample, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl,benzodithianyl, 3-(1-alkyl)-benzimidazol-2-onyl, and1,3-dihydro-imidazol-2-onyl.

The term “aryl” (or “aryl ring” or “aryl group”) used alone or as partof a larger moiety as in “aralkyl”, “aralkoxy”, “aryloxyalkyl”, or“heteroaryl” refers to both carbocyclic or heterocyclic aromatic ringsystems. The term “aryl” may be used interchangeably with the terms“aryl ring” or “aryl group”.

“Carbocyclic aromatic ring” groups have only carbon ring atoms(typically six to fourteen) and include monocyclic aromatic rings suchas phenyl and fused polycyclic aromatic ring systems in which two ormore carbocyclic aromatic rings are fused to one another. Examplesinclude 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Alsoincluded within the scope of the term “carbocyclic aromatic ring” or“carbocyclic aromatic”, as it is used herein, is a group in which anaromatic ring is “fused” to one or more non- aromatic rings (carbocyclicor heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic ring.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “aromatic heterocycle” or “heteroaromatic group”, used alone oras part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”,refer to heteroaromatic ring groups having five to fourteen members,including monocyclic heteroaromatic rings and polycyclic aromatic ringsin which a monocyclic aromatic ring is fused to one or more otheraromatic ring. Heteroaryl groups have one or more ring heteroatoms. Alsoincluded within the scope of the term “heteroaryl”, as it is usedherein, is a group in which an aromatic ring is “fused” to one or morenon-aromatic rings (carbocyclic or heterocyclic), where the radical orpoint of attachment is on the aromatic ring. Bicyclic 6,5 heteroaromaticring, as used herein, for example, is a six membered heteroaromatic ringfused to a second five membered ring, wherein the radical or point ofattachment is on the six membered ring. Examples of heteroaryl groupsinclude pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, forexample, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl,4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl,tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl,acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

As used herein, “cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”,include mono-, bi-, and tri-cyclic ring systems includingcycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl,each of which has been previously defined.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic carbocyclic aryls,and bicyclic heteroaryls.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocycloalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system canbe optionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, heteroaryl,alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, (carbocyclic aryl)carbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, “bridge” refers to a bond or an atom or an unbranchedchain of atoms connecting two different parts of a molecule. The twoatoms that are connected through the bridge (usually but not always, twotertiary carbon atoms) are denotated as “bridgeheads”.

As used herein, the term “spiro” refers to ring systems having one atom(usually a quaternary carbon) as the only common atom between two rings.

The term “ring atom” is an atom such as C, N, O or S that is in the ringof an aromatic group, cycloalkyl group or non-aromatic heterocyclicring.

A “substitutable ring atom” in an aromatic group is a ring carbon ornitrogen atom bonded to a hydrogen atom. The hydrogen can be optionallyreplaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to a moiety other thanhydrogen.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺(as in N-substituted pyrrolidinyl)).

As used herein an optionally substituted aralkyl can be substituted onboth the alkyl and the aryl portion. Unless otherwise indicated as usedherein optionally substituted aralkyl is optionally substituted on thearyl portion.

In some embodiments, an aliphatic or heteroaliphatic group, or anon-aromatic heterocyclic ring may contain one or more substituents.Suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic heterocyclic ring areselected from those listed above, for example, in the definitions ofJ^(A), J^(B), J^(C1), J^(D1), and J^(E1). Other suitable substitutentsinclude those listed as suitable for the unsaturated carbon of acarbocyclic aryl or heteroaryl group and additionally include thefollowing: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl),═NNHSO₂(alkyl), or ═NR*, wherein each R* is independently selected fromhydrogen or an optionally substituted C₁-6 aliphatic. Optionalsubstituents on the aliphatic group of R* are selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic),or halo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄aliphaticgroups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of anon-aromatic heterocyclic ring include those used above, for example, inthe definitions of J^(B), J^(D1) and J^(E1). Other suitable substituentsinclude —R⁺, -N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —l C(═S)N(R⁺)₂, —C(═NH)-N(R⁺)₂, or —NR⁺SO₂R⁺;wherein R⁺is hydrogen, an optionally substituted C₁₋₆ aliphatic,optionally substituted phenyl, optionally substituted —O(Ph), optionallysubstituted CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, two independent occurrences of R⁻,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺group is bound, form a 5-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group or the phenyl ring of R⁺areselected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic),O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), wherein each of theforegoing C₁₋₄aliphatic groups of R⁺is unsubstituted.

In some embodiments, a carbocyclic aryl (including aralkyl, aralkoxy,aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl andheteroarylalkoxy and the like) group may contain one or moresubstituents. Suitable substituents on the unsaturated carbon atom of acarbocyclic aryl or heteroaryl group are selected from those listedabove, for example, in the definitions of J^(A), J^(B), J^(C1), J^(D1)and J^(E1).Other suitable substituents include: halogen; —R°; —OR° ;—SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionallysubstituted with R^(o); —O(Ph) optionally substituted with R^(o);—(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph), optionallysubstituted with R^(o); -NO₂; —CN; -N(R^(o))₂; —NR^(o)C(O)R^(o);—NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂;—NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R_(o))₂; —OC(O)N(R^(o))₂;—OC(O)R^(o); —C(O)N(OR^(o)) R^(o); —C(NOR^(o)) R^(o); —S(O)₂R^(o);—S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); -N(OR^(o))R^(o); —C(═NH)-N(R^(o))₂; or—(CH₂)₀₋₂NHC(O)R^(o); wherein each independent occurrence of R^(o) isselected from hydrogen, optionally substituted C₁-6 aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph), or, two independent occurrences of R^(o), on thesame substituent or different substituents, taken together with theatom(s) to which each R^(o) group is bound, form a 5-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group of R° are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, CHO, N(CO)(C₁₋₄ aliphatic), C(O)N(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R^(o)is unsubstituted.

Non-aromatic nitrogen containing heterocyclic rings that are substitutedon a ring nitrogen and attached to the remainder of the molecule at aring carbon atom are said to be N substituted. For example, an N alkylpiperidinyl group is attached to the remainder of the molecule at thetwo, three or four position of the piperidinyl ring and substituted atthe ring nitrogen with an alkyl group. Non-aromatic nitrogen containingheterocyclic rings such as pyrazinyl that are substituted on a ringnitrogen and attached to the remainder of the molecule at a second ringnitrogen atom are said to be N′ substituted-N-heterocycles. For example,an N′ acyl N-pyrazinyl group is attached to the remainder of themolecule at one ring nitrogen atom and substituted at the second ringnitrogen atom with an acyl group.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a3-8-membered cycloalkyl ring. Exemplary rings that are formed when twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) are taken together with the atom(s) to which eachvariable is bound include, but are not limited to the following: a) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to the same atom and are taken togetherwith that atom to form a ring, for example,)N(R^(o))₂, where bothoccurrences of R^(o) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR⁰

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring.

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with said otheratom or group. Examples of such atoms or groups would include, but arenot limited to those listed in the definitions of Q¹, Y¹, Q² and Q³.Further examples include —NR—, —O—, —S—, —CO₂-, —OC(O)—, —C(O)CO—,—C(O)NR—, —C(═N—CN)—, —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂-, —NRC(O)NR—,—OC(O)NR—, —NRSO₂NR—, —SO—, or —SO₂-, wherein R is as defined above.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently -—H, C₁-C₆ aliphatic, a C₃₋₇non-aromatic carbocycle, a 5-6 membered carbocyclic aryl or heteroaryl,or a 4-7 membered non-aromatic heterocycle, each of which independentlybeing defined herein and being optionally substituted. Suitablesubstituents for the carbocycle, carbocyclic aryl, heteroaryl, andheterocycl are each independently include halogen, cyano, hydroxy, oxo,-NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—C(O)O—H, —C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)O(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ alkyl), and —C(O)N(C₁-C₆alkyl)₂, wherein each of said alkyl groups is optionally andindependently substituted with one or more substitutents selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄alkyl), and -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),—CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Suitable substituents forthe C₁-C₆ aliphatic (including C₁-C₆ alkyl) include halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl),—C(O)OH, —C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),—NHC(O)O(C₁-C₆ alkyl), —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂,phenyl, a 5-6 membered heteroaryl, a 5-6 membered non-aromaticheterocycle, and a C₃-C₇ carbocycle, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstitutents selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy,and wherein each of said phenyl, heteroaryl, heterocycle and carbocycleis optionally and independently substituted with one or moresubstitutents described above for the carbocycle, carbocyclic aryl,heteroaryl, and heterocycle represented by R^(X) and R^(Y). In someembodiments, each of R^(X) and R^(Y) is independently —H, an optionallysubstituted C₁₋₆ aliphatic group, or an optionally substituted C₃₋₈non-aromatic carbocycle. In some embodiments, each of R^(X) and R^(Y) isindependently —H or an optionally substituted C₁₋₆ aliphatic group. Insome embodiments, each of R^(x) and R^(Y) is independently -H or C₁-6alkyl optionally substituted with one or more substitutents selectedfrom the group consisting of halogen, cyano, hydroxy, oxo,-NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Examples of aminogroups include -NH₂, aliphatic amino, alkylamino, dialkylamino, orarylamino. As used herein, an “aliphatic amino” group refers to—NR^(X)R^(Y) wherein R^(X) is a C₁₋₆ aliphatic group optionallysubstituted as described above; and R^(Y) is —H or a C₁₋₆ aliphaticgroup optionally substituted as described above. As used herein, an“alkylamino” group refers to -NHR^(X) wherein R^(X) is a C₁₋₆ alkylgroup optionally substituted as described above. As used herein, a“dialkylamino” group refers to —NR^(X)R^(Y) wherein each of R^(X) andR^(Y) is independently a C₁₋₆ alkyl group optionally substituted asdescribed above. As used herein, an “arylamino” group refers to—NR^(X)R^(Y) wherein R^(X) is 5-6 membered, carbocyclic aryl orheteroaryl, and R^(Y) is —H or 5-6 membered, carbocyclic aryl orheteroaryl, wherein each of said carbocyclic aryl and heteroaryl groupsis independently and optionally substituted as described above. When theterm “amino” is not the terminal group (e.g., alkylcarbonylamino), it isrepresented by —NR^(X)—. R^(X) has the same meaning as defined above. Inone embodiment, the amino group is -NH₂ or an aliphatic amino. Inanother embodiment, the amino group is -NH₂, alkylamino or dialkylamino.In yet another embodiment, the amino group is -NH₂ or an arylamino. Inyet another embodiment, the amino group is -NH₂,-NH(C₁-C₆ alkyl) or-N(C₁-C₆ alkyl)₂, wherein each of the alkyl groups is optionally andindependently substituted with one or more substitutents selected fromthe group consisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄alkyl), -N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H,—CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refer to an amido group such as N(R^(X)R^(Y))—C(O)— orR^(Y)C(O)-N(R^(X))— when used terminally and —C(O)—N(R^(X))— or-N(R^(X))C(O)— when used internally, wherein R^(X) and R^(Y) are definedabove. Examples of amido groups include alkylamido (such asalkylcarbonylamino or alkylcarbonylamino or alkylaminocarbonyl),(heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido,(heterocycloalkyl)alkylamido, arylamido, aralkylamido,(cycloalkyl)alkylamido, or cycloalkylamido. In some embodiments, theamido group is —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or —C(O)NH(C₁-C₆ alkyl)₂, wherein eachof said alkyl is optionally and independently substituted with one ormore substitutents selected from the group consisting of halogen, cyano,hydroxy, oxo, -NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy. Insome embodiments, the amido group is —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or—C(O)NH(C₁-C₆ alkyl)₂, wherein each of the alkyl groups is optionallyand independently substituted with one or more substitutents selectedfrom the group consisting of halogen, cyano, hydroxy, oxo,-NH₂,-NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)are each independently as defined above.

As used herein, an “acyl” group refers to a formyl group or R^(X)C(O)—(such as -alkylC(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X) when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group, wherein R^(X) is as defined above.

The term “hydroxyl”or “hydroxy” or “alcohol moiety” refers to —OH.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as (alkyl—O)—C(O)—.

As used herein, a “carbonyl” refers to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, the term “alkoxy”, or “alkylthio”, as used herein,refers to an alkyl group, as previously defined, attached to themolecule through an oxygen (“alkoxy” e.g., —O-alkyl) or sulfur(“alkylthio” e.g., S-alkyl) atom.

As used herein, the terms “halogen”, “halo”, and “hal” mean F, Cl, Br,or I.

As used herein, the term “cyano” or “nitrile” refer to —or —C≡N.

The terms “alkoxyalkyl”, “alkoxyalkenyl”, “alkoxyaliphatic”, and“alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more alkoxy groups.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. This term includesperfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. In some embodiments, thecyanoalkyl is (NC)-alkyl-.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups, wherein the amino groupis as defined above. In some embodiments, the aminoaliphatic is a C₁-C₆aliphatic group substituted with one or more -NH₂ groups. In someembodiments, the aminoalkyl refers to the structure(R^(X)R^(Y))N-alkyl-, wherein each of R^(X) and R^(Y) independently isas defined above. In some specific embodiments, the aminoalkyl is C1C6alkyl substituted with one or more -NH₂ groups. In some specificembodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one ormore -NH₂ groups. In some embodiments, the aminoalkoxy is —O(C1-C6alkyl) wherein the alkyl group is substituted with one or more -NH₂groups.

The terms “hydroxyalkyl”, “hydroxyaliphatic”, and “hydroxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore —OH groups.

The terms “alkoxyalkyl”, “alkoxyaliphatic”, and “alkoxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore alkoxy groups. For example, an “alkoxyalkyl” refers to an alkylgroup such as (alkyl-O)-alkyl-, wherein alkyl is as defined above.

The term “carboxyalkyl” means alkyl substituted with one or more carboxygroups, wherein alkyl and carboxy are as defined above.

In some embodiments, each of the amino groups referred to in thedescriptions for the variables of Structural Formulae I-VI and XI(A)-XIV(e.g., R⁶, R⁷, J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above isindependently -NH₂, -NH(C₁-C₆ alkyl), -NH(C₃-C₆ carbocylce), —N(C₁-C₆alkyl)₂, or -N(C₁-C₆ alkyl)(C₃-C₆ carbocycle), wherein said alkyl andcarbocycle groups are each optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; each of the carboxy groups referred to in thedescriptions for the variables of Structural Formulae I-VI and XI(A)-XIV(e.g., R⁶, R⁷, J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above isindependently —C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), —C(O)O(C₃-C₆carbocycle), —OC(O)(C₃-C₆ carbocycle), or —CO₂H, wherein said alkyl andcarbocylce groups are each optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂, -NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; each of the amido groups referred to in thedescriptions for the variables of Structural Formulae I-VI and XI(A)-XIV(e.g., R⁶, R⁷, J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above isindependently —NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl),—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —NHC(O)(C₃-C₆ carbocycle),-N(C₁-C₆ alkyl)C(O)(C₃-C₆ carbocycle), —C(O)NH(C₃-C₆ carbocycle),—C(O)N(C₁-C₆ alkyl)(C₃-C₆ carbocycle), or —C(O)NH₂,wherein said alkyland carbocycle groups are each optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl),-N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy; each of the aminoalkyl groups referred to inthe descriptions for the variables of Structural Formulae I-VI andXI(A)-XIV (e.g., R⁸, R⁹, and R″) above is independently a C1-C6 alkylgroup substituted with one or more aminogroups independently selectedfrom the group consisting of -NH₂,-NH(C₁-C₄ alkyl), and -N(C₁-C₄alkyl)₂; and each of the aminoalkoxy groups referred to in thedescriptions for the variables of Structural Formulae I-VI and XI(A)-XIV(_(e.g., R) ⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R, R′, and R″) aboveis independently is a —O(C1-C6 alkyl) group wherein the alkyl group issubstituted with one or more one or more aminogroups independentlyselected from the group consisting of -NH₂,-NH(C₁-C₄ alkyl), and-N(C₁-C₄ alkyl)₂.

In some embodiments, each of the amino groups referred to in thedescriptions for the variables of Structural Formulae I-VI and XI(A)-XIV(e.g., R⁶, R⁷, J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above isindependently -NH₂, -NH(C₁-C₆ alkyl), or -N(C₁-C₆ alkyl)₂, wherein saidalkyl groups are each optionally and independently substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; each of the carboxy groups referred to in the descriptions forthe variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R⁶, R⁷,J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above is independently—C(O)O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), or —CO₂H, wherein said alkylgroups are each optionally and independently substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; each of the amido groups referred to in the descriptions for thevariables of Structural Formulae I-VI and XI(A)-XIV (e.g., R⁶, R⁷,J^(E1), R, R′, R″, R*, R^(a), R^(b) and R^(c)) above is independently—NHC(O)(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆ alkyl)₂, or —C(O)NH₂, wherein said alkyl groups areeach optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, -NH₂,-NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; each of the aminoalkyl groups referred to in the descriptionsfor the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R⁸,R⁹, and R″) above is independently a C1-C6 alkyl group substituted withone or more aminogroups independently selected from the group consistingof -NH₂,-NH(C₁-C₄ alkyl), and -N(C₁-C₄ alkyl)₂; and each of theaminoalkoxy groups referred to in the descriptions for the variables ofStructural Formulae I-VI and XI(A)-XIV (e.g., R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R, R′, and R″) above is independently is a —O(C₁-C₆alkyl) group wherein the alkyl group is substituted with one or more oneor more aminogroups independently selected from the group consisting of-NH₂,-NH(C₁-C₄ alkyl), and -N(C₁-C₄ alkyl)₂.

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orspecifically all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999 (and other editions of thebook), the entire contents of which are hereby incorporated byreference. The term “nitrogen protecting group”, as used herein, refersto an agent used to temporarily block one or more desired nitrogenreactive sites in a multifunctional compound. Preferred nitrogenprotecting groups also possess the characteristics exemplified for aprotecting group above, and certain exemplary nitrogen protecting groupsare also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in“Protective Groups in Organic Synthesis”, Third Edition, John Wiley &Sons, New York: 1999, the entire contents of which are herebyincorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, cis-trans,conformational, and rotational) forms of the structure. For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention, unless only one of the isomers is drawn specifically. Aswould be understood to one skilled in the art, a substituent can freelyrotate around any rotatable bonds. For example, a substituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, cis/trans, conformational, and rotational mixtures ofthe present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. For example, compounds ofStructural Formulae I-VI (e.g., Structural Formulae I, IA, II, III, IV,V, and VI) and XI(A)-XIV (e.g., Structural Formulae XIA, XIB, XIIA,XIIB, XIII, and XIV) that have -D at the position corresponding to R²are also within the scope of this invention. Such compounds are useful,for example, as analytical tools or probes in biological assays. Suchcompounds, especially deuterium analogs, can also be therapeuticallyuseful.

The terms “a bond” and “absent” are used interchangeably to indicatethat a group is absent.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Pharmaceutically Acceptable Salts, Solvates, Chlatrates, Prodrugs andOther Derivatives

The compounds described herein can exist in free form, or, whereappropriate, as salts. Those salts that are pharmaceutically acceptableare of particular interest since they are useful in administering thecompounds described below for medical purposes. Salts that are notpharmaceutically acceptable are useful in manufacturing processes, forisolation and purification purposes, and in some instances, for use inseparating stereoisomeric forms of the compounds of the invention orintermediates thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue side effects, such as, toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsdescribed herein include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds.

Where the compound described herein contains a basic group, or asufficiently basic bioisostere, acid addition salts can be preparedby 1) reacting the purified compound in its free-base form with asuitable organic or inorganic acid and 2) isolating the salt thusformed. In practice, acid addition salts might be a more convenient formfor use and use of the salt amounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like.

Where the compound described herein contains a carboxy group or asufficiently acidic bioisostere, base addition salts can be preparedby 1) reacting the purified compound in its acid form with a suitableorganic or inorganic base and 2) isolating the salt thus formed. Inpractice, use of the base addition salt might be more convenient and useof the salt form inherently amounts to use of the free acid form. Saltsderived from appropriate bases include alkali metal (e.g., sodium,lithium, and potassium), alkaline earth metal (e.g., magnesium andcalcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention alsoenvisions the quaternization of any basic nitrogen-containing groups ofthe compounds disclosed herein. Water or oil-soluble or dispersibleproducts may be obtained by such quaternization.

Basic addition salts include pharmaceutically acceptable metal and aminesalts. Suitable metal salts include the sodium, potassium, calcium,barium, zinc, magnesium, and aluminium. The sodium and potassium saltsare usually preferred. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are prepared frommetal bases which include sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide and the like. Suitable amine baseaddition salts are prepared from amines which are frequently used inmedicinal chemistry because of their low toxicity and acceptability formedical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N, N′-dibenzylethylenediamine,chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and thelike.

Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

In addition to the compounds described herein, pharmaceuticallyacceptable solvates (e.g., hydrates) and clathrates of these compoundsmay also be employed in compositions to treat or prevent the hereinidentified disorders.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds described herein.The term solvate includes hydrates (e.g., hemihydrate, monohydrate,dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound described herein ora salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, he term “clathrate” means a compound described herein ora salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule (e.g., a solvent or water)trapped within.

In addition to the compounds described herein, pharmaceuticallyacceptable derivatives or prodrugs of these compounds may also beemployed in compositions to treat or prevent the herein identifieddisorders.

A “pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable ester, salt of an ester or other derivativeor salt thereof of a compound described herein which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or an inhibitorily activemetabolite or residue thereof. Particularly favoured derivatives orprodrugs are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofthe invention that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds described herein that comprise -NO, -NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

A “pharmaceutically acceptable derivative” is an adduct or derivativewhich, upon administration to a patient in need, is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof. Examples of pharmaceuticallyacceptable derivatives include, but are not limited to, esters and saltsof such esters.

Pharmaceutically acceptable prodrugs of the compounds described hereininclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutical Compositions

The compounds described herein can be formulated into pharmaceuticalcompositions that further comprise a pharmaceutically acceptablecarrier, diluent, adjuvant or vehicle. In one embodiment, the presentinvention relates to a pharmaceutical composition comprising a compoundof the invention described above, and a pharmaceutically acceptablecarrier, diluent, adjuvant or vehicle. In one embodiment, the presentinvention is a pharmaceutical composition comprising an effective amountof a compound of the present invention or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, diluent,adjuvant or vehicle. Pharmaceutically acceptable carriers include, forexample, pharmaceutical diluents, excipients or carriers suitablyselected with respect to the intended form of administration, andconsistent with conventional pharmaceutical practices.

An “effective amount” includes a “therapeutically effective amount” anda “prophylactically effective amount”. The term “therapeuticallyeffective amount” refers to an amount effective in treating and/orameliorating an influenza virus infection in a patient infected withinfluenza. The term “prophylactically effective amount” refers to anamount effective in preventing and/or substantially lessening thechances or the size of influenza virus infection outbreak. Specificexamples of effective amounts are described above in the sectionentitled Uses of Disclosed Compounds.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, e.g.,non-toxic, non-inflammatory, non-immunogenic or devoid of otherundesired reactions or side-effects upon the administration to asubject. Standard pharmaceutical formulation techniques can be employed.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as usedherein, includes any and all solvents, diluents, or other liquidvehicle, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds describedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. As used herein,the phrase “side effects” encompasses unwanted and adverse effects of atherapy (e.g., a prophylactic or therapeutic agent). Side effects arealways unwanted, but unwanted effects are not necessarily adverse. Anadverse effect from a therapy (e.g., prophylactic or therapeutic agent)might be harmful or uncomfortable or risky. Side effects include, butare not limited to fever, chills, lethargy, gastrointestinal toxicities(including gastric and intestinal ulcerations and erosions), nausea,vomiting, neurotoxicities, nephrotoxicities, renal toxicities (includingsuch conditions as papillary necrosis and chronic interstitialnephritis), hepatic toxicities (including elevated serum liver enzymelevels), myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins (such as humanserum albumin), buffer substances (such as twin 80, phosphates, glycine,sorbic acid, or potassium sorbate), partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes (such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, or zinc salts), colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methylcellulose,hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil;corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Administration Methods

The compounds and pharmaceutically acceptable compositions describedabove can be administered to humans and other animals orally, rectally,parenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, or drops), bucally, as an oral ornasal spray, or the like, depending on the severity of the infectionbeing treated.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are specificallysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Specifically, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions described herein may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,specifically, as solutions in isotonic, pH adjusted sterile saline,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The compounds for use in the methods of the invention can be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for subjects undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form can be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form can be the same or different foreach dose.

-   Exemplification

Preparation of Compounds

The compounds disclosed herein, including those of Structural FormulaeI-VI (e.g., Structural Formulae I, IA, II, III, IV, V, and VI) andXI(A)-XIV (e.g., Structural Formulae XIA, XIB, XIIA, XIIB, XIII, andXIV) can be prepared by any suitble method known in the art, forexample, WO 2005/095400 and WO 2007/084557. For example, the compoundsdepicted in FIGS. 3-8 can be prepared by any suitble method known in theart, for example, WO 2005/095400 and WO 2007/084557, and by theexemplary syntheses descrbied below. In particular, the compoundsdepicted in FIG. 8 can be prepared as described in WO 2005/095400 and WO2007/084557. Syntheses of certain exemplary compounds of StructuralFormulae I-VI and XI(A)-XIV are described below. Generally, thecompounds of Structural Formulae I-VI and XI(A)-XIV can be prepared asshown in those syntheses optionally with any desired appropriatemodification.

General Analytical Methods.

As used herein the term RT (min) refers to the LCMS retention time, inminutes, associated with the compound. Unless otherwise indicated, themethod employed to obtain the reported retention times is as follows:

-   -   Column: YMC-Pack Pro Cig, 50 mm×4.6 mm id

Gradient: 10-95% methanol/H₂O. Flow rate: 1.5 ml/min. UV-vis detection.

Methodology for Synthesis and Characterization of Compounds

Syntheses of certain exemplary compounds of Structural Formulae I-VI(e.g., Structural Formulae I, IA, II, III, IV, V, and VI) and XI(A)-XIV(e.g., Structural Formulae XIA, XIB, XIIA, XIIB, XIII, and XIV) aredescribed below. NMR and Mass Spectroscopy data of certain specificcompounds are summarized in Tables 1-5.

Formation of (S)-tert-butyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(1b).

To a solution of5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,1a, (3.5 g, 7.5 mmol) and tert-butyl(3S)-3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL)was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reactionmixture was heated at 90° C. for 75 minutes. The mixture was cooled toroom temp and diluted into aqueous saturated NH₄Cl solution andextracted with EtOAc. The organic phase was washed with brine (3 times),dried (MgSO₄), filtered and concentrated under vacuo. The resultingresidue was purified via silica gel chromatography (0%-10% MeOH/CH₂Cl₂)to afford the desired product 1b as a white solid.

LCMS RT=4.6 (M+1) 601.5, (M−1) 599.6.

Formation of(S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine(1c).

To a solution of tert-butyl(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate,1b, (2.1 g, 3.5 mmol) in CH₂Cl₂ (30 mL) was added trifluoroacetic acid(20 mL). After stirring the reaction mixture at room temperature for 75min, the mixture was concentrated under vacuo. The crude residue wasdiluted with EtOAc and neutralized with 1N sodium hydroxide solution.The aqueous phase was separated and extracted again with EtOAc. Thecombined organic phases were dried (MgSO₄), filtered and concentratedunder vacuo to afford the desired product (1c) as a light yellow solid.

¹H NMR (300 MHz, d6-DMSO) δ 8.76 (d, J=2.5, Hz, 1H), 8.50 (d, J=2.5 Hz,1H), 8.44 (s, 1H), 8.27 (d, J=4.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.66(d, J=6.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 4.17 (m, 1H), 3.17 (dd,J=3.1, 11.8 Hz, 1H), 2.99-2.94 (m, 1H), 2.67-2.60 (m, 1H), 2.38-2.34 (m,1H), 2.06-2.02 (m, 1H), 1.77-1.73 (m, 1H) and 1.63-1.50 (m, 2H) ppm.LCMS RT=2.1 (M+1) 501.5, (M−1) 499.5.

Formation of1-((S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-2-ol(1d).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine,1c, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane(0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwavereactor at 140° C. for 5 minutes. The reaction was evaporated to drynessand the resulting residue was purified via silica gel chromatography(0-10% MeOH: CH₂Cl₂) to afford the desired product (1d).

¹H NMR (300 MHz, d6-DMSO) δ 8.78 (d, J=2.5 Hz, 1H), 8.49 (d, J=2.4 Hz,1H), 8.43 (d, J=1.2 Hz, 1H), 8.26 (d, J=3.9 Hz, 1H), 8.07 (d, J=8.4 Hz,2H), 7.60 (d, J=7.5 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 4.54-4.50 (m, 1H),4.20 (m, 1H), 3.35-3.17 (m, 1H), 3.33 (s, 3H), 3.25 (m, 1H), 3.19 (d,2H), 3.00 (m, 1H), 2.75 (d, J=11.8 Hz, 1H), 2.44-2.26 (m, 4H), 1.93 (m,1H), 1.73 (m, 2H), 1.63 (m, 1H) and 1.23 (m, 1H) ppm.

LCMS RT=2.4 (M+1) 589.6.

Formation of1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-2-ol(537).

To a solution of1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol,1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reactionmixture was heated in a microwave reactor at 120° C. for 5 minutes. Thereaction mixture was diluted with water and the aqueous phase wasextracted with EtOAc (twice). The combined organic phases were dried(MgSO₄), filtered and concentrated under vacuo. The resulting solid waspurified by silica gel chromatography (5-20% MeOH: CH₂Cl₂) to afford thedesired product (537) as a white solid.

¹H NMR (300 MHz, d6-DMSO DMSO) δ 12.35 (s, 1H), 8.73 (d, J=2.4 Hz, 1H),8.29 (d, J=2.4 Hz, 1H), 8.19-8.09 (m, 2H), 7.36 (d, J=7.5 Hz, 1H), 4.53(dd, J=4.5, 8.0 Hz, 1H), 4.27 (s, 1H), 3.77-3.72 (m, 1H), 3.36-3.20 (m,3H), 3.22 (s, 3H), 3.03-2.97 (m, 1H), 2.76 (d, J=10.6 Hz, 1H), 2.44-2.14(m, 2H), 2.08 (m, 2H), 1.99-1.94 (m, 1H), 1.71-1.63 (m, 2H), 1.44 (m,1H) and 1.23-1.15 (m, 1H) ppm.

LCMS RT=1.6 (M+1) 435.5.

Other analogs that can be prepared in the same manner as 537 aredescribed below:

3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propane-1,2-diol(525)

¹H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 4.51 (m, 1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35(s, 2H), 3.08-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.47-2.25 (m, 2H),2.22-2.12 (m, 2H), 1.99-1.90 (m, 1H), 1.70-1.60 (m, 2H) and 1.45 (m, 1H)ppm.

LCMS RT=1.5 (M+1) 421.5.

1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-isopropoxypropan-2-ol(551).

¹H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.19-8.16 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 4.42-4.37(m, 2H), 3.70 (s, 1H), 3.52-3.42 (m, 1H), 3.35-3.25 (m, 1H), 2.99 (m,1H), 2.73 (m, 1H), 2.43-2.11 (m, 4H), 1.94 (m, 1H), 1.75-1.60 (m, 2H),1.52-1.40 (M, 1H) and 1.10-0.99 (m, 6H).

LCMS RT=1.7 (M+1) 463.4, (M−1) 461.5.

(S)-1-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)butan-2-ol(538).

¹H NMR (300 MHz, d6-DMSO) δ 12.53 (s, 1H), 10.32 (s, 1H), 8.69 (dd,J=2.5, 5.2 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.31 (m, 2H), 7.97 (s, 1H),4.76 (m, 1H), 3.92 (m, 2H), 3.84-3.55 (m, 2H), 3.40-2.80 (m, 3H),2.14-1.90 (m, 3H), 1.80-1.74 (m, 2H), 1.65 (m, 1H), 1.43-1.23 (m, 2H)and 0.96-0.85 (m, 3H) ppm.

LCMS RT=1.6 (M+1) 419.6.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2-methylpropan-2-ol(546).

¹H NMR (300 MHz, CDCl₃) δ 9.60 (s, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.33 (d,J=2.3 Hz, 1H), 8.17 (d, J=2.7 Hz, 1H), 8.09 (d, J=3.3 Hz, 1H), 5.34 (d,J=11.5 Hz, 1H), 4.45-4.42 (m, 1H), 3.09 (d, J=11.3 Hz, 1H), 2.75-2.59(m, 4H), 2.40 (s, 2H), 1.94-1.70 (m, 4H) and 1.27 (s, 6H) ppm.

LCMS RT=1.6 (M+1) 419.5.

(R)-3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propane-1,2-diol(588).

¹H NMR (300 MHz, DMSO) δ 12.31 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.27 (d,J=2.4 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J=4.0 Hz, 1H), 7.33 (d, J=7.8 Hz,1H), 4.47-4.44 (m, 1H), 4.35 (d, J=4.0 Hz, 1H), 4.28-4.17 (m, 1H),3.64-3.62 (m, 1H), 3.17 (d, J=5.2 Hz, 1H), 3.02-2.98 (m, 1H), 2.78-2.73(m, 1H), 2.37 (ddd, J=12.8, 5.2, 5.2 Hz, 2H), 2.22-2.10 (m, 2H),1.99-1.89 (m, 1H), 1.73-1.63 (m, 2H) and 1.46-1.43 (m, 1H) ppm. LCMSRT=1.5 (M+1) 421.4. LCMS RT=1.6 (M+1) 419.3.

(S)-3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propane-1,2-diol(587).

¹H NMR (300 MHz, DMSO) δ 12.31 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.28 (d,J=2.4 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J=4.0 Hz, 1H), 7.33 (d, J=7.5 Hz,1H), 4.34 (s, 1H), 4.27-4.23 (m, 1H), 3.62 (s, 1H), 3.35 (d, J=5.5 Hz,1H), 3.06-3.03 (m, 1H), 2.78-2.74 (m, 1H), 2.44 (d, J=5.0 Hz, 1H), 2.27(dd, J=12.9, 6.9 Hz, 1H), 2.20-2.07 (m, 2H), 2.05-1.90 (m, 1H),1.75-1.59 (m, 2H) and 1.49-1.39 (m, 1H) ppm.

1-((3S,4S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4-methylpiperidin-1-yl)-3-methoxypropan-2-ol(550).

¹H NMR (300 MHz, d6-DMSO) δ 12.33 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.22-8.20 (m, 2H), 6.72-6.62 (m, 1H), 4.61 (dd,J=4.2, 10.0 Hz, 1H), 4.54 (m, 1H), 3.75-3.71 (m, 1H), 3.34-3.22 (m, 1H),3.22 (d, 3H), 2.88-2.42 (m, 4H), 2.41-2.25 (m, 4H), 1.93 (m, 1H), 1.56(m, 2H) and 0.90 (d, J=6.7 Hz, 3H). LCMS RT=1.6 (M+1) 449.5.

3-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2-hydroxypropanamide(603).

¹H NMR (300 MHz, DMSO) δ 12.31 (s, 1H), 8.71 (d, J=2.4 Hz, 1H),8.28-8.25 (m, 1H), 8.19-8.16 (m, 2H), 7.34-7.30 (m, 1H), 7.19 (s, 1H),7.11 (s, 1H), 4.24 (s, 1H), 3.99 (dd, J=3.5, 7.6 Hz, 1H), 3.01 (d,J=10.3 Hz, 1H), 2.81-2.63 (m, 2H), 2.36-2.29 (m, 2H), 1.71 (s, 3H) and1.51-1.44 (m, 2H) ppm.

Formation of (S)-tert-butyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(2a).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine,1c, (0.25 g, 0.50 mmol) in DMF was added tert-butylbromoacetate (0.08mL, 0.55 mmol) and Na₂CO₃ (0.11 g, 0.99 mmol). The reaction mixture wasstirred at room temperature for 6 h. The resulting thick whiteprecipitate was diluted with aqueous saturated NaCl solution and washedwith water. The white solid was dissolved in CH₂Cl₂ and the solution wasdried (MgSO₄), filtered and concentrated in vacuo. The crude waspurified via silica gel chromatography (0%-5% MeOH/CH₂Cl₂) to afford thedesired product, 2a, as a white solid.

¹H NMR (300 MHz, d6-DMSO) δ 8.76 (d, J=2.4 Hz, 1H), 8.48 (d, J=3.6 Hz,1H), 8.44 (s, 1H), 8.26 (d, J=3.9 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.59(d, J=8.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 4.18 (m, 1H), 3.19 (s, 2H),3.03-2.99 (m, 1H), 2.78-2.73 (m, 1H), 2.45-2.30 (m, 2H), 2.37 (s, 3H),1.99-1.93 (m, 1H), 1.80-1.60 (m, 2H), 1.46-1.40 (m, 1H) and 1.36 (s, 9H)ppm.

LCMS RT=2.8 (M+1) 615.6, (M−1) 613.6.

Formation of (S)-tert-butyl2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)ethanoate(2b).

To a solution of tert-butyl2-[(3S)-3-[[2-[5—chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate,2a, (0.27 g, 0.44 mmol) in THF was added 1N LiOH solution. The reactionmixture was heated in microwave at 120 degrees for 10 minutes. Thereaction mixture diluted with brine, extracted with EtOAc, then with 20%isopropanol/CH₂Cl₂. The combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo. The resulting product, 2b, was usedwithout further purification. LCMS RT=2.0 (M+1) 461.5.

Formation of(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-ypethanoicacid (577).

To a solution tert-butyl2-[(3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate,2b, (0.12 g, 0.26 mmol) in CH₂Cl₂ (4 mL) was added trifluoroacetic acid(4 mL). The reaction mixture was stirred at room temperature for 18 hand concentrated in vacuo. The crude residue was diluted with5%MeOH/CH₂Cl₂ and the resulting white precipitate was filtered andwashed with CH₂Cl₂ to afford the desired product, 577, astrifluoroacetic acid salt.

¹H NMR (300 MHz, d6-DMSO) δ 12.46 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.36(d, J=2.3 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.29 (d, J=3.9 Hz, 1H), 7.79(d, J=7.0 Hz, 1H), 4.70-4.50 (m, 1H), 4.21 (s, 2H), 3.80-3.70 (m, 1H),3.55-3.47 (m, 1H), 3.20-2.90 (m, 2H), 2.10-1.95 (m, 3H) and 1.69-1.60(m, 1H) ppm. LCMS RT=1.9 (M+1) 405.4.

Other analogs that can be prepared in the same manner as 577:

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)ethanamide(567).

¹H NMR (300 MHz, d6-DMSO) δ 12.29 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.41 (d, J=7.7Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 4.35-4.29 (m, 1H), 2.98-2.75 (m,1H), 2.92 (d, J=6.8 Hz, 2H), 2.68 (d, J=10.8 Hz, 1H), 2.29-2.19 (m, 2H),1.96-1.92 (m, 1H), 1.80-1.65 (m, 2H) and 1.53-1.42 (m, 1H) ppm. LCMSRT=2.1 (M+1) 404.4, (M−1) 402.5.

2-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propanamide(583).

¹H NMR (300 MHz, d6-DMSO) δ 8.70 (d, J=2.3 Hz, 1H), 8.52 (d, J=8.7 Hz,1H), 8.35 (dd, J=5.0, 6.5 Hz, 2H), 4.10 (dd, J=2.7, 7.0 Hz, 1H),3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 2.35-2.45 (m, 1H), 2.15-2.35 (m,1H), 1.80-1.95 (m, 1H), and 1.60-1.65 (m, 3H) ppm.

LCMS (M+1) 418.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanopyrimidin-4-ylamino)piperidin-1-yl)ethanamide(654).

LCMS RT=2.9 (M+1) 411.4, (M−1) 409.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrimidin-4-ylamino)piperidin-1-yl)ethanamide(620).

LCMS RT=1.9 (M+1) 400.4, (M−1) 398.3.

2-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propanoicacid (573).

¹H NMR (300 MHz, d6-DMSO) δ 12.51 (s, 1H), 10.28-10.00 (m, 1H), 8.70 (s,1H), 8.38 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.30 (d, J=4.2 Hz, 1H),7.89-7.75 (m, 1H), 4.70-4.50 (m, 1H), 4.33-4.29 (m, 1H), 3.79-3.45 (m,2H), 3.20-2.80 (m, 2H), 2.12-1.95 (m, 3H), 1.72-1.60 (m, 1H) and 1.52(d, J=5.5 Hz, 3H) ppm.

2-((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-N-methylpropanamide (606).

¹H NMR (300 MHz, d6-DMSO) δ 8.69 (d, J=12.7 Hz, 1H), 8.54-8.49 (m, 1H),8.32 (dd, J=4.8, 7.2 Hz, 2H), 4.83-4.76 (m, 1H), 4.02 (m, 1H), 3.95-3.71(m, 2H), 3.31-3.10 (m, 1H), 2.86 (s, 3H), 2.33 (d, J=9.9 Hz, 1H),2.40-2.14 (m, 3H), 1.94 (s, 1H), 1.66-1.58 (m, 3H) and 1.10 (d, J=6.5Hz, 3H) ppm.

LCMS (M+1) 432.2.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2-methylpropanoicacid (590).

¹H NMR (300 MHz, MeOD) δ 8.81 (d, J=2.3 Hz, 1H), 8.19 (t, J=2.5 Hz, 2H),7.98 (d, J=4.2 Hz, 1H), 4.48 (s, 1H), 2.90 (d, J=10.1 Hz, 1H), 2.74-2.66(m, 2H), 2.60 (d, J=5.7 Hz, 1H), 1.89-1.83 (m, 2H), 1.67 (s, 1H), 1.25(d, J=4.9 Hz, 6H) ppm. LCMS (M+1) 433.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2-methylpropanamide(598).

LCMS RT=1.8 (M+1) 432.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-N,2-dimethylpropanamide(599).

¹H NMR (300 MHz, MeOD) δ 8.86 (d, J=2.4 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H),8.17 (s, 1H), 8.03 (d, J=4.1 Hz, 1H), 4.46 (dd, J=4.7, 8.8 Hz, 1H), 4.10(q, J=7.2 Hz, 1H), 3.05 (d, J=12.8 Hz, 1H), 2.66 (s, 3H), 2.34 (dd,J=11.3, 20.6 Hz, 2H), 2.08 (d, J=12.3 Hz, 1H), 1.89-1.71 (m, 2H),1.66-1.54 (m, 1H) and 1.19 (s, 6H) ppm.

LCMS (M+1) 433.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-N,N,2-trimethylpropanamide(600).

¹H NMR (300 MHz, MeOD) δ 8.81 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H),8.14 (s, 1H), 8.02 (d, J=4.0 Hz, 1H), 4.45-4.37 (m, 1H), 3.61 (s, 3H),2.97 (d, J=8.8 Hz, 1H), 2.80 (s, 3H), 2.72 (s, 1H), 2.39 (t, J=10.0 Hz,2H), 2.15 (dd, J=3.6, 12.7 Hz, 1H), 1.91-1.79 (m, 2H), 1.53-1.47 (m, 1H)and 1.28 (s, 6H) ppm.

LCMS (M+1) 460.5.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-N-(2-methoxyethyl)-2-methylpropanamide(601).

¹H NMR (300 MHz, MeOD) δ 8.88 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H),8.17 (s, 1H), 8.02 (d, J=4.1 Hz, 1H), 4.47-4.41 (m, 1H), 3.38 (dd,J=1.6, 4.8 Hz, 4H), 3.12-3.07 (m, 1H), 2.73 (d, J=10.8 Hz, 1H),2.35-2.29 (m, 2H), 2.19-2.15 (m, 1H), 1.91-1.80 (m, 2H), 1.55 (s, 1H),1.37 (s, 1H) and 1.20 (s, 6H) ppm.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-N-cyclopropyl-2-methylpropanamide(602).

¹H NMR (300 MHz, MeOD) δ 8.82 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H),8.15 (s, 1H), 8.01 (d, J=4.0 Hz, 1H), 4.41 (m, 1H), 3.02 (d, J=10.0 Hz,1H), 2.59-2.47 (m, 1H), 2.40-2.30 (m, 2H), 2.09-2.01 (m, 1H), 1.89-1.85(m, 1H), 1.78-1.66 (m, 1H), 1.61-1.55 (m, 1H), 1.26-1.16 (m, 1H), 1.10(d, J=6.6 Hz, 6H), 0.68-0.63 (m, 2H) and 0.44-0.40 (m, 2H) ppm.

LCMS (M+1) 472.4.

Formation of(S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyrimidin-4-amine(3a).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine,1c, (0.17 g, 0.34 mmol) in DMF (1.5 mL) was added 2,2,2-trifluoroethyltrichloromethanesulfonate (0.19 g, 0.68 mmol), followed by ^(i)Pr₂NEt(0.24 mL, 1.36 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The mixture was poured into brine and extractedtwice with EtOAc. The combined organic phases were washed twice withbrine, dried (MgSO₄), filtered, and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂)afforded the desired product, 3a, as a white solid.

¹H NMR (300 MHz, d6-DMSO) δ 8.77 (d, J=2.4 Hz, 1H), 8.48 (d, J=2.4 Hz,1H), 8.42 (s, 1H), 8.27 (d, J=3.9 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.62(d, J=7.5 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 4.17 (m, 1H), 3.30-3.18 (m,3H), 2.90 (m, 1H), 2.44-2.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H),1.72-1.57 (m, 2H) and 1.51-1.40 (m, 1H) ppm.

LCMS RT=4.6 (M+1) 583.4, (M−1) 581.4.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyrimidin-4-amine(668).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-1-(2,2,2-trifluoroethyl)-3-piperidyl]pyrimidin-4-amine,3a, (0.10 g, 0.18 mmol) in THF was added 1M LiOH (0.90 mL, 0.90 mmol)solution. The reaction mixture was heated in microwave at 120° C. for 10minutes. The reaction mixture was diluted with brine, extracted withEtOAc, then with 20% isopropanol/CH₂Cl₂. The combined organic phaseswere dried (MgSO₄), filtered and concentrated in vacuo. The resultingresidue was purified via silica gel chromatography (0-10% MeOH:CH₂Cl₂)to afford the desired product, 1339, as a white solid.

¹H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.38 (d, J=7.7 Hz, 1H), 4.22-4.17(m, 1H), 3.31-3.16 (m, 3H), 2.90 (m, 1H), 2.40 (t, J=10.2 Hz, 2H),2.00-1.95 (m, 1H), 1.77-1.60 (m, 2H) and 1.50-1.38 (m, 1H) ppm.

LCMS RT=3.5 (M+1) 429.4, (M−1) 427.4.

Other analogs that can be prepared in the same manner as 668:

Synthesis of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(2,2-difluoroethyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(1).

¹H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 4.51 (m, 1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35(s, 2H), 3.08-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.47-2.25 (m, 2H),2.22-2.12 (m, 2H), 1.99-1.90 (m, 1H), 1.70-1.60 (m, 2H) and 1.45 (m, 1H)ppm.

LCMS RT=2.7 (M+1) 411.4, (M−1) 409.4.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(2,2-difluoroethyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(595).

¹H NMR (300 MHz, d6-DMSO) δ 12.32 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.28(d, J =2.4 Hz, 1H), 8.18-8.15 (m, 2H), 7.32 (d, J=7.1 Hz, 1H), 4.20 (d,J=7.1 Hz, 1H), 3.46 (t, J=5.8 Hz, 2H), 3.19 (s, 3H), 3.10-3.06 (m, 1H),2.82-2.78 (m, 1H), 2.57-2.50 (m, 2H), 2.11-1.95 (m, 3H), 1.71-1.63 (m,2H) and 1.48-1.35 (m, 1H) ppm.

LCMS RT=1.7 (M+1) 405.4, (M−1) 403.4.

(S)-2-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)ethanenitrile(669).

¹H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 4.30-4.20(m, 1H), 3.80 (s, 2H), 3.07-3.03 (m, 1H), 2.82-2.73 (m, 1H), 2.29-2.10(m, 2H), 2.05-1.96 (m, 1H), 1.87-1.65 (m, 2H) and 1.49-1.40 (m, 1H)ppm.; LCMS RT=2.3 (M+1) 386.1, (M−1) 384.2.

Formation of(S)-N-(1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (4a).

To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo [5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c,(0.16 g, 0.32 mmol) in 1,2-dichloroethane (2 mL) was added1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops ofacetic acid and Na(OAc)₃BH (0.10 g, 0.49 mmol) . The reaction mixturewas heated at 60° C. for 18 h. The mixture was cooled to roomtemperature and diluted with aqueous saturated NaHCO₃ solution. Theaqueous phase was extracted twice with EtOAc. The combined organicphases were dried (MgSO₄), filtered and concentrated in vacuo. The cruderesidue was purified via silica gel chromatography (0-20% MeOH/CH₂Cl₂)to afford the product, 4a.

¹H NMR (300 MHz, d6-DMSO) δ 11.83 (s, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.48(d, J=2.4 Hz, 1H), 8.41 (s, 1H), 8.25 (d, J=3.8 Hz, 1H), 8.07 (d, J=8.3Hz, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.00-6.80 (m,2H), 4.22 (m, 1H), 3.58 (dd, J=18.9, 13.8 Hz, 2H), 2.95 (m, 1H),2.75-2.72 (m, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.99-1.93 (m, 1H),1.78-1.55 (m, 2H) and 1.45-1.30 (m, 1H) ppm.

Formation of(S)-N-(1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(589).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-1-(1H-imidazol-2-ylmethyl)-3-piperidyl]pyrimidin-4-amine,4a, (0.08 g, 0.13 mmol) in THF (2.5 mL) was added 1M LiOH (0.67 mL, 0.65mmol) solution. The reaction mixture was heated in microwave at 120° C.for 10 minutes. The mixture was cooled to room temperature and dilutedwith brine. The aqueous phase was extracted with CH₂Cl₂, then twice with20% isopropanol/ CH₂Cl₂.The combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo to afford the desired product, 589,as a white solid.

¹H NMR (300 MHz, d6-DMSO) δ 8.77 (d, J=2.4 Hz, 1H), 8.48 (d, J=2.4 Hz,1H), 8.42 (s, 1H), 8.27 (d, J=3.9 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.62(d, J=7.5 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 4.17 (m, 1H), 3.30-3.18 (m,3H), 2.90 (m, 1H), 2.44-2.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H),1.72-1.57 (m, 2H) and 1.51-1.40 (m, 1H) ppm.

LCMS RT=1.6 (M+1) 427.4.

Other analogs which can be prepared in the same manner as 589:

N-(1-((1H-imidazol-5-yl)methyl)piperidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(594).

¹H NMR (300 MHz, d6-DMSO) δ 12.31 (s, 1H), 11.86-11.77 (m, 1H), 8.70 (d,J=2.2 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.15 (d, J=3.9 Hz, 1H), 8.10 (d,J=2.5 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 4.19(m, 1H), 3.57 (d, J=13.8 Hz, 1H), 3.48 (d, J=13.8 Hz, 1H), 3.04 (d,J=8.3 Hz, 1H), 2.80 (d, J=10.4 Hz, 1H), 2.10-1.90 (m, 3H), 1.72-1.62 (m,2H) and 1.51-1.35 (m, 1H) ppm; LCMS RT=1.6 (M+1) 427.4, (M−1) 425.4.

Formation of tert-butyl(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate(5a).

To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (8.1 g,40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) inisopropanol (80 mL) was added N,N-diisopropyl-N-ethylamine (9.0 mL, 51.7mmol). The reaction mixture was warmed to 80° C. and stirred for 17hours. All volatiles were removed at reduced pressure and the residuewas dissolved in EtOAc. The organic layer was partitioned with water andthe layers were separated. The organic phase was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. The resulting residuewas dissolved in CH₂Cl₂ and purified by silica gel chromatography (0-50%EtOAc/Hexanes) to afford the desired product, 5a.

LCMS RT=3.3 (M+1) 331.1.

Formation of tert-butyl(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate(1b).

To a solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(1.8 g, 4.2 mmol) and tert-butyl(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate,5a, (1.2 g, 3.7 mmol) in DME (15 mL) and H₂O (5 mL) was added K₂CO₃ (1.7g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. To themixture was added tetrakis triphenylphosphine palladium(O) (0.2 g, 0.2mmol) and the reaction mixture was heated at 90° C. for 3 days. Thereaction was cooled down to room temperature and then diluted withEtOAc/H₂O. The layers were separated and the organic phase was washedwith brine, dried (MgSO₄), filtered and evaporated to dryness. Theresulting residue was dissolved in CH₂Cl₂ and purified by silica gelchromatography (0-100% EtOAc/Hexanes) to afford the desired product, 1b.

LCMS RT=4.6 (M+1) 601.2.

Formation of tert-butyl(3S)-3-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate(2b).

To a solution of tert-butyl(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate,1b, (0.93 g, 1.55 mmol) in methanol (10 mL) was added sodium methoxide(10 mL of 1M solution). The reaction mixture was warmed to 45° C. Afterstirring for 30 minutes the reaction was to cooled to room temperatureand quenched by additon into water. The mixture was diluted with EtOAcand the layers were separated. The organic phase was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. The resulting residuewas purified by silica gel chromatography (0-100% EtOAc /Hexanes) toafford the desired product, 2b.

LCMS RT=2.8 (M+1) 447.2.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine(5b).

To a suspension of tert-butyl(3S)-3-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate,2b, (0.45 g, 1.01 mmol) in isopropanol (3 mL) was added propan-2-olhydrochloride (1.5 mL of 5M solution, 7.500 mmol). The reaction mixturewas warmed to 80° C. and stirred for 3 hours. The mixture was cooled toroom temperature and all volatiles were removed at reduced pressure. Theresulting crude product, 5b, was used without further purification.

LCMS RT=1.5 (M+1) 347.1.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-amine(389).

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.04 g, 0.11 mmol) in CH₂Cl₂ (1.4 mL) and DMF (0.30mL) was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followedby methanesulfonyl chloride (0.02 g. 0.20 mmol). The reaction mixturewas allowed to stir at room temperature for 17 hours. The mixture wasconcentrated in vacuo, dissolved in 1 mL of DMSO and purified bypreparatory HPLC (0.1% ammonium formate-H₂O/acetonitrile) to afford thedesired product, 389.

LCMS RT=1.8 (M+1) 425.3.

Other analogs that can be prepared in the same manner as 389:

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(ethylsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(393).

LCMS RT=1.8 (M+1) 439.3.

(S)-N-(1-(butylsulfonyl)piperidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(390).

LCMS RT=2.1 (M+1) 467.3.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(391).

LCMS RT=1.9 (M+1) 451.3.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(isopropylsulfonyl)-piperidin-3-yl)pyrimidin-4-amine(394).

LCMS RT=1.9 (M+1) 453.3.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopentylmethylsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(392).

LCMS RT=2.3 (M+1) 493.5.

Formation of(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(propylsulfonyl)piperidin-3-yl)pyrimidin-4-amine(316).

To a solution of 2-(5-chloro-1H-pyrrolo [2,3 —b]pyridin-3—yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine, 5c, (0.40 g, 1.15mmol) in 10:1 mixture of CH₂Cl₂/DMF (8 mL) was added ^(i)Pr₂NEt (0.60mL, 3.46 mmol) followed by 1-propanesulfonyl chloride (0.13 mL, 1.15mmol). The reaction mixture was stirred at room temperature for 5 hours.The resulting residue was purified by preparatory HPLC(0.1%TFA-H₂O/acetonitrile) to afford the desired product, 316.

LCMS RT=2.5 (M+1) 453.3.

Other analogs that can be prepared in the same manner as 316:

(R)-2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-N-(1-(ethylsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine(321).

LCMS RT=2.7 (M+1) 439.1.

(R)-2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(isopropylsulfonyl)-piperidin-3-yl)pyrimidin-4-amine(322).

LCMS RT=2.9 (M+1) 453.1.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(propylsulfonyl)-piperidin-3-yl)pyrimidin-4-amine(306).

LCMS RT=2.9 (M+1) 453.2.

Formation of(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(cyclobutyl)methanone(395).

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.04 g, 0.11 mmol) in CH₂Cl₂ (1.40 mL) and DMF (300p. was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followedby cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reactionmixture was allowed to stir at room temperature for 17 hours. Themixture was concentrated in vacuo, dissolved in 1 mL of DMSO andpurified by preparatory HPLC (0.1% ammonium formate- H₂O/acetonitrile)to afford the desired product, 395.

LCMS RT=1.9 (M+1) 429.3.

Other analogs that can be prepared in the same manner as 395:

(S)-1-(3-(2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)propan-1-one(435).

LCMS RT=1.8 (M+1) 403.4.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2-methylpropan-1-one(436)

LCMS RT=1.9 (M+1) 417.4.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-2,2-dimethylpropan-1-one(437)

LCMS RT=2.0 (M+1) 431.4.

(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(cyclopropyl)methanone(451)

LCMS RT=1.8 (M+1) 415.4.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-1-one(396)

LCMS RT=1.7 (M+1) 433.3.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-ypethanone(434)

LCMS RT=1.6 (M+1) 389.4.

(R)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methylbutan-1-one(318)

LCMS RT=2.9 (M+1) 431.1.

(R)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(cyclopropyl)methanone(317)

LCMS RT=2.7 (M+1) 415.1.

(R)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-tluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-1-one(320)

LCMS RT=2.5 (M+1) 433.1.

(R)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(cyclobutyl)methanone(319)

LCMS RT=2.8 (M+1) 429.1.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-tluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methylbutan-1-one(332)

LCMS RT=2.0 (M+1) 431.2.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone(485)

LCMS RT=1.9 (M+1) 371.5.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-tluoropyrimidin-4-ylamino)piperidin-1-yl)-2-methoxyethanone(486)

LCMS RT=1.9 (M+1) 401.5.

(S)-methyl4-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-4-oxobutanoate(487)

LCMS RT=2.0 (M+1) 443.9.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)-3-methoxypropan-1-one(488)

LCMS RT=1.9 (M+1) 415.5.

(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-3-methylbutan-1-one(489)

LCMS RT=2.1 (M+1) 413.5.

Formation of(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(1-methylcyclopropyl)methanone(445)

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.04 g, 0.10 mmol) in CH₂Cl₂ (1.4 mL) and DMF (0.3mL) was added N,N-diisopropyl-N-ethylamine (0.3 mL, 1.72 mmol), followedby 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-aminehydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02g, 0.12 mmol) and 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12mmol). The mixture was concentrated in vacuo, dissolved in 1 mL of DMSOand purified by preparatory HPLC (0.1% ammoniumformate-H₂O/acetonitrile) to afford the desired product, 445.

LCMS RT=2.1 (M+1) 429.5.

Analogs that can be prepared in the same manner as 445:

(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)(3-methyloxetan-3-yl)methanone(444)

LCMS RT=1.7 (M+1) 445.4.

Formation of(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-isopropylpiperidine-1-carboxamide(439).

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.042 g, 0.100 mmol) in CH₂Cl₂ (1.4 mL) and DMF (0.3mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol)followed by isocyanatopropane (0.120 mmol). The reaction mixture wasstirred at room temperature for 17 hours. The mixture was concentratedin vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC(0.1% ammonium formate-H₂O/acetonitrile) to afford the desired product,439.

LCMS RT=1.8 (M+1) 432.4.

Other analogs that can be prepared in the same manner as 439:

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-ethylpiperidine-1-carboxamide(438).

LCMS RT=1.7 (M+1) 418.4.

Formation of3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-propylpiperidine-1-carboxamide(196).

To a solution of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine,5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CH₂Cl₂/pyridine (2 mL) wasadded propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture wasstirred at room temperature for 12 hours. The resulting residue waspurified by preparatory HPLC (0.1%TFA-H₂O/acetonitrile) to afford thedesired product, 196.

LCMS RT=2.6 (M+1) 432.1, (M−1) 430.1.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-propylpiperidine-1-carboxamide(324).

LCMS RT=2.6 (M+1) 432.2.

(S)-N-butyl-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxamide(323).

LCMS RT=2.7 (M+1) 446.2.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxamide(507).

LCMS (TFA buffer): Rt 1.69 min, ES' 390.

Formation of (S)-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(440).

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.042 g, 0.100 mmol) in CH₂Cl₂ (1.4 mL) and DMF (0.3mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol)followed by methyl chloroformate (0.009 g, 0.120 mmol). The reactionmixture was stirred at room temperature for 17 hours. The mixture wasconcentrated in vacuo, dissolved in 1 mL of DMSO and purified bypreparatory HPLC (0.1% ammonium formate- H₂O/acetonitrile) to afford thedesired product, 440.

LCMS RT=1.8 (M+1) 405.4.

Analogs that can be prepared in the same manner as 440:

(S)-ethyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(441).

LCMS RT=1.9 (M+1) 419.4.

(S)-isopropyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(442).

LCMS RT=2.1 (M+1) 433.4.

Formation of (S)-((S)-tetrahydrofuran-3-yl) 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylate(443).

To a solution of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-aminehydrochloride, 5b, (0.042 g, 0.100 mmol) in CH₂Cl₂ (1.4 mL) and DMF (0.3mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol)followed by (2,5-dioxopyrrolidin-1-yl)[(3S)-tetrahydrofuran-3-yl]carbonate (0.028 g, 0.120 mmol). The reactionmixture was stirred at room temperature for 17 hours. The mixture wasconcentrated in vacuo, dissolved in 1 mL of DMSO and purified bypreparatory HPLC (0.1% ammonium formate-H₂O/acetonitrile) to afford thedesired product, 443.

LCMS RT=1.8 (M+1) 463.3.

Formation of tert-butyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate (6a).

A mixture of 2,4-dichloro-5-fluoro-pyrimidine (0.97 g, 5.81 mmol) and^(i)Pr₂NEt (2.53 mL, 14.50 mmol) in THF (50 mL) was treated withtert-butyl 3-aminoazetidine-1-carboxylate (1.00 g, 5.81 mmol) andstirred at room temperature until complete by LCMS. The mixture wasconcentrated to dryness then diluted with water and extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to afford an oil that was purified by silica gelchromatography (0-100% petroleum ether/EtOAc gradient). Removal of thesolvent under reduced pressure afforded 3.36g (89% yield) of a whitesolid after vacuum drying.

LCMS: RT=3.2 min, ES⁺ 303.

Formation of tert-butyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate(6b).

A solution of tert-butyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate, 6a, (0.39g, 1.28 mmol) and5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.60 g, 1.39 mmol) in DME (10 mL) and 2M Na₂CO₃ (5 mL) was degassedwith argon (3× vacuum and back fill) then treated with catalyticPd(PPh₃)₄ and the mixture heated at 80° C. under argon. After 3 h thesolvent was concentrated to a reduced volume then diluted with EtOAc andfiltered through florisil (40 mL pad) and washed with EtOAc. The solventwas concentrated in vacuo and the resulting dark residue purified withsilica-gel chromatography (0-100% petroleum ether/EtOAc gradient) toafford 230 mg (32% yield) of 6b, as white-pink solid.

LCMS: RT=4.7 min, ES⁺ 573.

Formation ofN-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-₃4)-5-fluoropyrimidin-4-aminehydrochloride (6c).

A suspension of tert-butyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate,6b, (0.23 g, 0.40 mmol) in methanol (10 mL) was treated with 4NHCl/dioxane (5 mL, 20 mmol) then heated at 80° C. for 30 minutes. Thesolvent was removed and the residue dried under vacuum to afford 240 mgof a solid that was used without purification.

LCMS RT=2.4 min, ES⁺ 473.

Formation of (S)-tetrahydrofuran-3-yl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate(422).

A suspension ofN-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-aminehydrochloride, 6c, (0.06 g, 0.11 mmol) in THF (1 mL) was treated with^(i)Pr₂NEt (0.30 mL, 1.70 mmol) then solid (S)-2,5-dioxopyffolidin-1-yltetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. Theresulting mixture was stirred for 2 hours at room temperature and thenquenched with 200 L of morpholine and evaporated to dryness to afford(S)-tetrahydrofuran-3-yl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate,6d, which was used without purification.

LCMS RT=3.8 min, ES⁺588.

(S)-tetrahydrofuran-3-yl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate,6d, was dissolved in methanol (2 mL) and then treated with of 25% sodiummethoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube. LCMSshowed complete reaction after 10 minutes. The resulting solution wasquenched with aqueous saturated NH₄C₁ solution (0.5mL) then evaporatedto dryness and the residue dissolved in DMSO and purified by reversephase HPLC (ammonium formate buffer) to afford 25.9 mg (55% yield) ofthe desired product, 422, as a solid.

LCMS RT=1.8 min, ES⁺433.

Formation of2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(propylsulfonyl)azetidin-3-yl)pyrimidin-4-amine(423).

To a stirred suspension ofN-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-aminehydrochloride, 6c, (0.055 g, 0.110 mmol) in THF (1 mL) was added^(i)Pr₂NEt (0.300 mL, 1.720 mmol) followed by propane-1-sulfonylchloride (0.012 mL, 0.108 mmol). The resulting homogenous light yellowsolution mixture was heated at 50° C. for one hour at which time LCMSshowed complete reaction. Morpholine (0.20 mL) was added and thesolution evaporated to dryness. The resulting residue was dissolved inmethanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL)and heated at 60° C. in sealed tube for 10 minutes. The resultingsolution was quenched with aqueous saturated NH₄Cl solution (0.5mL) thenevaporated to dryness. The resulting residue was dissolved in DMSO andpurified by reverse phase HPLC (ammonium formate buffer) to afford 19.8mg (43% yield) of the desired product, 423, as a solid.

LCMS RT=2.6 min, ES⁺425.

Other analogs that can be prepared in a manner similar to 423:

Formation of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopentyl-methylsulfonyl)azetidin-3-yl)-5-fluoropyrimidin-4-amine(469).

To a stirred solution ofN-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-aminehydrochloride, 6c, (0.03 g, 0.06 mmol) in dichloromethane (1 mL) wasadded^(i)Pr₂NEt (0.33 μL, 1.90 mmol) followed bycyclopentylmethanesulfonyl chloride (0.01 g, 0.06 mmol). The resultingmixture was stirred 30 minutes at room temperature at which time LCMSshowed complete reaction. Morpholine (0.20 mL) was added and thesolution evaporated to dryness. The resulting residue was dissolved inmethanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL)and heated at 60° C. in sealed tube for 10 minutes. The solution wasquenched with aqueous saturated NH₄Cl solution (0.5mL) then evaporatedto dryness. The resulting residue was dissolved in DMSO and purified byreverse phase HPLC (ammonium formate buffer) to afford 27.4 mg (88%yield) of the desired product, 469, as a solid. LCMS RT=3.1 min, ES⁺465.

Formation of1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidin-1-yl)-2-methoxyethanone(468).

According to the procedure for compound 469 using methoxyacetyl chlorideafforded 11.7 mg (51% yield) of 468, as a white solid.

LCMS RT=1.6 min, ES⁺ 390.

Formation of3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxamide(512).

According to the procedure for compound 469 using 61 mg (0.11mmol) of 6cand isocyanatotrimethylsilane (15.14 μL, 0.11 mmol) afforded 87 mg (79%yield) of 512, as a white solid:

LCMS RT=2.4 min, ES⁺ 362.

Formation of (S)-tert-butyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (7a).

To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol)and ^(i)Pr₂NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added tert-butyl(3S)-3-aminopyrrolidine-1-carboxylate (1.83 mL, 10.48 mmol) in THF (2mL). The resulting solution was allowed to stir at room temperature for2 hours. The mixture was concentrated to dryness, diluted withdichloromethane and washed with water. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to afford 3.41 g of 7a, as a whitefoamy solid.

LCMS RT=3.0 min. ES⁺ 317.

Formation of (S)-tert-butyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate(7b).

A solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(2.41 g, 5.60 mmol) and tert-butyl(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]pyrrolidine-1-carboxylate,7a, (1.69 g, 5.30 mmol) in DME (34 mL) and 2M Na₂CO₃ (8.5 mL) wasdegassed with nitrogen (5 min) then treated with Pd(PPh₃)₄ (0.31 g, 0.27mmol) then heated at 90° C. overnight. The resulting dark solution wasfiltered through florisil, washed with EtOAc then concentrated in vacuo.The resulting residue was purified by silica-gel chromatography (0-100%)petroleum ether: EtOAc gradient. Removal of the solvent under reducedpressure afforded 1.33g (42% yield) of a white solid after vacuumdrying.

LCMS RT=4.4 min. ES⁺ 588.

Formation of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine(7c).

A solution of tert-butyl(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]pyrrolidine-1-carboxylate,7b, (1.33 g, 2.27 mmol) in THF (25 mL) was treated with hydrogenchloride (12 mL of 4M solution in dioxane, 48.00 mmol) at roomtemperature. The reaction was then heated at 90° C. until LCMS showedreaction was complete. The mixture was concentrated to dryness thendried under vacuum to afford 1.04g (88% yield) of 7c, as a tan solid.

LCMS RT=2.3 min. ES⁺ 487.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine(398).

To a stirred suspension of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-aminehydrochloride, 7c, (0.05 g, 0.10 mmol) in THF (1 mL) was added^(i)Pr₂NEt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride(0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture washeated at 50° C. for one hour at which time LCMS showed completereaction. Morpholine (0.20 mL) was added and the solution evaporated todryness. The resulting residue was dissolved in methanol (2 mL) thentreated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C.in sealed tube until LCMS showed reaction was complete. The resultingsolution was quenched with aqueous saturated NH₄Cl (0.5mL) thenevaporated to dryness. The residue was dissolved in DMSO and purified byreverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37%yield) of 398, as a solid.

LCMS RT=1.7 min. ES⁺411.

Other analogs that can be prepared in a manner similar to 398:

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(ethylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine(399).

According to the procedure for compound 398 using 50 mg (0.10 mmol) of7c and ethanesulfonyl chloride (54 μL, 0.57 mmol) afforded 21.7mg (49%yield) of 399, as a solid.

LCMS RT=1.8 min. ES⁺425.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(isopropylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine(400).

According to the procedure for compound 398 using 2-propanesulfonylchloride (82 mg, 0.57 mmol) afforded 17.9 mg (39% yield) of 400, as asolid.

LCMS RT=1.9 min. ES⁺439.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine(401).

According to the procedure for compound 398 using cyclopropanesulfonylchloride (81 mg, 0.57 mmol) afforded 17.1 mg (37% yield) of 401, as asolid.

LCMS RT=1.9 min. ES⁺ 437.

Formation of(S)-N-(1-(butylsulfonyl)pyrrolidin-3-yl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(402).

According to the procedure for compound 398 using 1-butanesulfonylchloride (90 mg, 0.57 mmol) afforded 21 mg (45% yield) of 402, as asolid.

LCMS RT=2.1 min. ES⁺ 453.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopentylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine(403).

According to the procedure for compound 398 using cyclopentanesulfonylchloride (97 mg, 0.57 mmol) afforded 9.7 mg (20% yield) of 403, as asolid.

LCMS RT=2.1 min. ES⁺ 465.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(1-(propylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine(410).

According to the procedure for compound 398 using propylsulfonylchloride (20 mg, 0.14 mmol) afforded 15.5 mg (36% yield) of 410, as asolid.

LCMS RT=2.0 min. ES⁺ 439.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopentylmethylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine(479).

According to the procedure for compound 398 using cyclopentylmethylsulfonyl chloride (30 mg, 0.16 mmol) afforded 26.7 mg (58% yield) of479, as a solid.

LCMS RT=2.3 min. ES⁺ 479.

Formation of (S)-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate(476).

According to the procedure for compound 398 using methylchloroformate(20 mg, 0.21 mmol) afforded 13.6 mg (52% yield) of 476, as atrifluoroacetic acid salt after preparatory HPLC purification.

LCMS (ammonium formate buffer) RT=2.6 min. ES⁺ 391.

Formation of (S)-isopropyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate(477).

According to the procedure for compound 476 using isopropylchloroformate (20 mg, 0.21 mmol) afforded 11.3 mg (42% yield) of 477, asa trifluoroacetic acid salt after preparatory HPLC purification.

LCMS (ammonium formate buffer) RT=2.0 min. ES⁺ 419.

Formation of (3S)-(tetrahydrofuran-3-yl)methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate(484).

According to the procedure for compound 398 using2,5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl)methyl carbonate (0.023g, 0.096 mmol) afforded 5.7 mg (10% yield) of 484, as a trifluoroaceticacid salt after preparatory HPLC purification.

LCMS (ammonium formate buffer) RT=2.6 min. ES⁺ 461.

Formation of((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydrofuran-3-yl)methanone(478).

According to the procedure for compound 398 usingtetrahydrofuran-3-carboxylic acid (35 mg, 0.30 mmol) afforded 22.2 mg(52% yield) of 478, as a solid.

LCMS (TFA buffer) RT=1.6 min. ES⁻ 431.

Formation of(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-ypethanone(480).

According to the procedure for compound 398 using acetyl chloride (45uL, 0.64 mmol) afforded 4.2 mg (18% yield) of 480, as a solid.

LCMS (TFA buffer) RT=1.6 min, ES⁻ 375.

Formation of(S)-1-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-yl)-2-methoxyethanone(481).

According to the procedure for compound 398 using methoxyacetyl chloride(50 mg, 0.46 mmol) afforded 8.6 mg (33% yield) of 481, as a solid.

LCMS (TFA buffer) RT=1.6 min, ES⁻ 405.

Formation of(S)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-yl)(3-methyloxetan-3-yl)methanone(482).

According to the procedure for compound 398 using3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) afforded 17.7 mg(42% yield) of 482, as a solid.

LCMS (TFA buffer) RT=1.6 min, ES⁺ 431.

Formation of((S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-yl)(morpholin-2-yl)methanone(483).

According to the procedure for compound 398 using morpholine2-carboxylic acid (25 mg, 0.11 mmol) afforded 3.6 mg (8% yield) of 483as a solid.

LCMS (TFA buffer): Rt 1.4 min, ES⁺ 446.

Using a procedure equivalent to that for the preparation of 7c, theother enantiomer (8a) can be obtained.

Analogs that can be prepared from compound 8a.

Formation of (R)-((S)-tetrahydrofuran-3-yl) 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-1-carboxylate(424).

According to the procedure for compound 398 using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate and (S)-2,5-dioxopyrrolidin-1-yltetrahydrofuran-3-yl carbonate afforded 19.8 mg (47% yield) of 424 as asolid.

LCMS (TFA buffer) RT=1.8 min, ES⁻ 447.

Formation of(R)-(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-1-yl)(3-methyloxetan-3-yl)methanone(473).

According to the procedure for compound 482 using(R)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(pyrrolidin-3-yl)pyrimidin-4-aminehydrochloride, 8a, and 3-methyloxetane-3-carboxylic acid (50 mg, 0.46mmol) afforded 18.6 mg (44% yield) of 473, as a solid.

LCMS (TFA buffer) RT=1.6 min, ES⁻ 431.

Formation of(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(1-(cyclopropylmethyppyrrolidin-3-yl)-5-fluoropyrimidin-4-amine(415).

A solution of(S)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(pyrrolidin-3-yl)pyrimidin-4-aminehydrochloride, 7c, (0.05 g, 0.10 mmol) in methanol (3 mL) was treatedwith cyclopropane carboxaldehyde (0.30 mmol), sodium cyanoborohydride(0.30 mmol) and potassium acetate (0.04 g, 0.30 mmol) then stirred at60° C. until the reaction was complete. Aqueous workup afforded an oilthat was dissolved in methanol (2 mL) then treated with of 25% sodiummethoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube. LCMSshowed complete reaction. The resulting solution was quenched withaqueous saturated NH₄Cl solution (0.5 mL) then evaporated to dryness andthe residue dissolved in DMSO and purified by reverse phase HPLC(ammonium formate buffer) to afford 6.2 mg (17% yield) of 415 as asolid.

LCMS RT=1.5 min, ES⁺ 387.

Formation ofN-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-1-(methylsulfonyl)azepan-4-amine(496).

According to the procedure for compound 398 using methanesulfonylchloride afforded the desired product, 496, as a solid.

LCMS RT=1.8 min, ES⁺ 439.

Formation of1-(4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azepan-1-ypethanone(497).

According to the procedure for compound 398 using acetyl chlorideafforded the desired product, 497, as a solid.

LCMS RT=1.7 min, ES⁺ 403.

Formation of methyl4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azepane-1-carboxylate(498).

According to the procedure for compound 398 using methyl chloroformateafforded the desired product, 498, as a solid.

LCMS RT=1.9 min, ES⁺ 419.

Formation of4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N,N-dimethylazepane-1-carboxamide(499).

According to the procedure for compound 398 using dimethyl carbamoylchloride afforded desired product, 499, as a solid.

LCMS RT=1.8 min, ES⁺ 432.

Formation of4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azepane-1-carboxamide(509).

According to the procedure for compound 398 usingtrimethylsilylisocyanate afforded desired product, 509, as a solid.

LCMS RT=1.6 min, ES⁺ 404.

Formation of4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-methylazepane-1-carboxamide(506).

According to the procedure for compound 398 using methyl isocyanateafforded the desired product, 506, as a hydrochloride salt aftertreating with HCl/dioxane.

LCMS RT=2.1 min, ES⁺ 418.

Formation of (R)-tert-butyl3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate(11a).

To a solution of 2,4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and(R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (0.56 g, 2.59mmol) in THF (50 mL) was added ^(i)Pr₂NEt (0.45 mL, 2.59 mmol). Thereaction mixture was heated at 80° C. at for 8 h. The solvent wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (5-30% EtOAc/hexanes) to affordthe desired product, 11a.

LCMS (M+1) 345.1.

Formation of (R)-tert-butyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(11b)

To a degassed solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.71 g, 1.65 mmol), (R)-tert-butyl3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate,11a, (1.19 g, 3.60 mmol) and aqueous K₂CO₃ (2.48 mL of 2 M solution,4.97 mmol) in THF (30 mL) was addedbis(tri-tert-butylphosphine)palladium(0) (0.17 g, 0.33 mmol). Thereaction mixture was degassed for an additional 15 min. The mixture wasstirred at room temperature for 4 hours, concentrated in vacuo, and theresulting crude residue was purified by silica gel chromatography(10%-80% EtOAc/hexanes) to afford the desired product, 11b.

LCMS (M+1) 461.4, (M−1) 460.7.

Formation of2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyppyrimidin-4-amine(11c).

To a solution of (R)-tert-butyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate,11b, (0.13 g, 2.8 mmol) in 5% MeOH/CH₂Cl₂ was added 0.7 ml 4N solutionof HCl/dioxane. The reaction mixture was stirred at room temperature for12 hours. The resulting precipitate was filtered and used withoutfurther purification.

LCMS (M+1) 361.1.

Formation of(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3-methoxypropan-1-one(327).

To a solution of2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine,11c, (0.04 g, 0.11 mmol) in a 10:1 mixture of CH₂Cl₂/DMF (1 mL) wasadded ^(i)Pr₂NEt (0.058 mL, 0.33 mmol) and 3-methoxypropanoyl chloride(0.02 g, 0.17 mmol). After 12 hours, the solvent was concentrated invacuo and the resulting crude was and the crude was purified bypreparatory HPLC (0.1%TFA-H₂O/acetonitrile) to afford the desiredproduct, 327.

LCMS (M+1) 447.3.

Other analogs that can be prepared in the same manner as 327:

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone(113).

LCMS RT=2.9 (M+1) 479.4, (M−1) 477.6.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-(thiophen-2-ypethanone(104).

LCMS RT=2.8 (M+1) 485.3, (M−1) 483.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3,5-difluorophenyl)methanone(108).

LCMS RT=2.1 (M+1) 501.3.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-ypethanone(111).

LCMS RT=2.5 (M+1) 403.4.

(R)-benzo[b]thiophen-2-yl(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)methanone(107).

LCMS RT=3.2 (M+1) 521.3.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-ypethanone(37).

LCMS RT=2.5 (M+1) 403.3.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(furan-2-yl)methanone(102).

LCMS RT=2.7 (M+1) 455.3, (M−1) 453.3.

(R)-2-(benzyloxy)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-ypethanone(106).

LCMS RT=3.0 (M+1) 509.3, (M−1) 507.5.

(R)-2-fluoroethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(126).

LCMS RT=2.1 (M+1) 451.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(thiophen-2-yl)methanone(97).

LCMS RT=2.9 (M+1) 471.2, (M−1) 469.6.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2,2-dimethylpropan-1-one(105).

LCMS RT=3.0 (M+1) 445.3, (M−1) 443.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,3-dimethylphenyl)methanone(157).

LCMS RT=2.0 (M+1) 493.1.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-phenoxyethanone(94).

LCMS RT=2.9 (M+1) 495.3, (M−1) 493.5.

(R)-2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-oxoethylethanoate (110).

LCMS RT=2.5 (M+1) 461.3, (M−1) 459.4.

(S)-ethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(33).

LCMS RT=3.0 (M+1) 433.3, (M−1) 431.4.

(R)-prop-1-en-2-yl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(74).

LCMS RT=3.1 (M+1) 445.2, (M−1) 443.4.

(R)-3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonyl)pyrazine-2-carboxylicacid (82).

LCMS RT=1.6 (M+1) 511.3.

(1S,2R)-2-((R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonyl)cyclopropanecarboxylicacid (83).

LCMS RT=1.6 (M+1) 473.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-methoxyethanone(45).

LCMS RT=2.4 (M+1) 433.3, (M−1) 431.4.

(S)-allyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(17).

LCMS RT=3.1 (M+1) 445.3, (M−1) 443.4.

(R)-prop-2-ynyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(122).

LCMS RT=2.9 (M+1) 443.3, (M−1) 441.5.

(S)-ethyl5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-5-oxopentanoate(19).

LCMS RT=2.8 (M+1) 503.4, (M−1) 501.5.

(R)-but-2-ynyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(127).

LCMS RT=3.1 (M+1) 457.3, (M−1) 455.6.

(S)-methyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(23).

LCMS RT=2.8 (M+1) 419.3, (M−1) 417.3.

(R)-allyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(119).

LCMS RT=3.1 (M+1) 445.4, (M−1) 443.5.

(S)-but-2-ynyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(30).

LCMS RT=3.1 (M+1) 457.3, (M−1) 455.6.

(R)-tert-butyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(15).

LCMS RT=2.7 (M+1) 461.3.

(S)-isobutyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(28).

LCMS RT=3.3 (M+1) 461.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)propan-1-one(32).

LCMS RT=1.9 (M+1) 417.2.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-methylpropan-1-one(34).

LCMS RT=3.2 (M+1) 447.4, (M−1) 445.5.

(S)-isopropyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(35).

LCMS RT=3.0 (M+1) 447.3, (M−1) 445.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(cyclopentyl)methanone(99).

LCMS RT=3.1 (M+1) 457.3, (M−1) 455.4.\

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)but-2-en-1-one(41)

LCMS RT=2.7 (M+1) 429.3, (M−1) 427.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3,3-dimethylbutan-1-one(42)

LCMS RT=3.1 (M+1) 459.3, (M−1) 457.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3,3,3-trifluoropropan-1-one(44)

LCMS RT=2.8 (M+1) 471.3, (M−1) 469.4.

(S)-2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-N,N,N-trimethyl-2-oxoethanaminium(43)

LCMS RT=2.4 (M+1) 460.3, (M−1) 458.5.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-(dimethylamino)ethanone(46)

LCMS RT=2.2 (M+1) 446.4, (M−1) 444.5.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-(pyridin-3-ypethanone(47)

LCMS RT=2.4 (M+1) 480.3, (M−1) 478.6.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)but-3-en-1-one(49)

LCMS RT=2.7 (M+1) 429.3, (M−1) 427.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-(1H-tetrazol-1-yl)ethanone(48)

LCMS RT=2.4 (M+1) 471.3, (M−1) 469.4.

(R)-5-((S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonyl)dihydrofuran-2(3H)-one(51)

LCMS RT=1.7 (M+1) 472.9.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4ylamino)methyl)piperidin-1-yl)-2-(1H-imidazol-1-ypethanone (50)

LCMS RT=2.3 (M+1) 469.3, (M−1) 467.4.

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)pent-4-yn-1-one(52)

LCMS RT=1.9 (M+1) 441.3.

(R)-5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-5-oxopentanoicacid (53)

LCMS RT=1.8 (M+1) 475.3, (M−1) 473.4.

(R)-2-(2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-oxoethoxy)ethanoicacid (54)

LCMS RT=1.7 (M+1) 477.3, (M−1) 475.4.

(1S,3R)-3-((R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonyl)cyclopentanecarboxylicacid (55)

LCMS RT=2.5 (M+1) 501.3, (M−1) 499.6.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-fluorophenyl)methanone(58)

LCMS RT=2.9 (M+1) 483.3, (M−1) 481.5.

(R)-5-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3,3-dimethyl-5-oxopentanoicacid (80)

LCMS RT=1.9 (M+1) 503.3.

2-chloro-1-((R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)propan-1-one(93)

LCMS RT=2.9 (M+1) 451.2, (M−1) 449.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(cyclohexyl)methanone(95)

LCMS RT=3.2 (M+1) 471.3, (M−1) 449.4.

(R)-tert-butyl 3-((2-(5-amino-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(114)

LCMS RT=2.7 (M+1) 461.3.

(R)-ethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(495)

LCMS RT=1.7 (M+1) 385.4.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-methoxyethanone(491)

LCMS RT=1.7 (M+1) 415.4.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)-3-methoxypropan-1-one(493)

LCMS RT=1.7 (M+1) 429.5.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)-3-methylbutan-1-one(494)

LCMS RT=1.9 (M+1) 427.5.

(S)-2-methoxyethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(24)

LCMS RT=2.8 (M+1) 463.2, (M−1) 461.3.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-phenylethanone(56)

LCMS RT=2.9 (M+1) 479.3, (M−1) 477.4.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one(57)

LCMS RT=2.8 (M+1) 443.3, (M−1) 441.4.

(R)-4-(methoxycarbonyl)phenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(63)

LCMS RT=3.2 (M+1) 539.3, (M−1) 537.4.

(R)-phenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(68)

LCMS RT=3.2 (M+1) 481.4, (M−1) 479.4.

(R)-2-chlorophenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(70)

LCMS RT=3.3 (M+1) 515.3, (M−1) 513.3.

(R)-2-methoxyphenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(69)

LCMS RT=3.2 (M+1) 511.3.

(R)-p-tolyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(71)

LCMS RT=3.4 (M+1) 495.3, (M−1) 493.4.

(R)-3-(trifluoromethyl)phenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(72)

LCMS RT=3.5 (M+1) 549.3, (M−1) 547.4.

(R)-4-fluorophenyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(73)

LCMS RT=3.3 (M+1) 499.3, (M−1) 497.4.

(R)-2-(1-(2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-oxoethyl)cyclopentypethanoicacid (81)

LCMS RT=2.0 (M+1) 529.3.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-chlorophenyl)methanone(84)

LCMS RT=2.0 (M+1) 499.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3,4-difluorophenyl)methanone(85)

LCMS RT=2.1 (M+1) 501.3.

(R)-2-chloro-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)ethanone(92)

LCMS RT=2.7 (M+1) 437.2, (M−1) 435.3.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,6—dichlorophenyl)methanone(96)

LCMS RT=2.9 (M+1) 535.2, (M−1) 533.2.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-(4-fluorophenypethanone(98)

LCMS RT=2.9 (M+1) 497.3, (M−1) 495.4.

(R)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-cyclopentylethanone(100)

LCMS RT=3.1 (M+1) 471.3, (M−1) 469.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(pyrazin-2-yl)methanone(111)

LCMS RT=2.5 (M+1) 467.2, (M−1) 465.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(furan-2-yl)methanone(186)

LCMS RT=2.7 (M+1) 455.3, (M−1) 453.3.

(R)-benzo[d][1,3]dioxol-5-yl(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)methanone(103)

LCMS RT=2.8 (M+1) 509.3, (M−1) 507.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,4-difluorophenyl)methanone(152)

LCMS RT=2.8 (M+1) 501.3, (M−1) 499.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-(methylamino)phenyl)methanone(112)

LCMS RT=3.0 (M+1) 494.3, (M−1) 492.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3,4-dimethoxyphenyl)methanone(109)

LCMS RT=2.7 (M+1) 525.3, (M−1) 523.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3,5-difluorophenyl)methanone(86)

LCMS RT=2.8 (M+1) 501, (M−1) 499.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(6-tluoro-4H-benzo[d][1,3]dioxin-8-yl)methanone(142)

LCMS RT=2.8 (M+1) 541.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(o-tolyl)methanone(143)

LCMS RT=2.9 (M+1) 479.4, (M−1) 477.6.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-(trifluoromethyl)phenyl)methanone(146)

LCMS RT=3.0 (M+1) 533.3, (M−1) 531.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,3-dihydrobenzofuran-6-yl)methanone(145)

LCMS RT=2.9 (M+1) 507.3, (M−1) 505.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,4-dichlorophenyl)methanone(147)

LCMS RT=3.2 (M+1) 533.3, (M−1) 531.4.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-ethoxyphenyl)methanone(158)

LCMS RT=3.0 (M+1) 509.4, (M−1) 507.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-methoxy-3-methylphenyl)methanone(148)

LCMS RT=3.0 (M+1) 509.3, (M−1) 507.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,5-difluorophenyl)methanone(151)

LCMS RT=2.9 (M+1) 501.2, (M−1) 499.5.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-phenoxyphenyl)methanone(150)

LCMS RT=3.2 (M+1) 557.3, (M−1) 555.6.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2,4-dimethoxyphenyl)methanone(154)

LCMS RT=2.3 (M+1) 525.3, (M−1) 523.2.

(R)-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(cyclopropyl)methanone(325)

LCMS RT=2.7 (M+1) 429.2.

(R)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone(272)

LCMS RT=2.5 (M+1) 461.3.

(R)-1-(3-((5-fluoro-2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)ethanone (268)

LCMS RT=2.1 (M+1) 369.3.

(R)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)(phenyl)methanone(271)

LCMS RT=2.5 (M+1) 431.4.

(R)-1-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)butan-1-one(270)

LCMS RT=2.4 (M+1) 397.3.

(R)-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)(phenyl)propan-1-one(269)

LCMS RT=2.3 (M+1) 383.3.

(S)-1-(3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)butan-1-one(225)

LCMS RT=2.4 (M+1) 397.4.

In a manner analogous to that of the preparation of compound 327,compounds with the opposite absolute stereochemistry, were prepared asfollows:

Formation of(S)-N-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamide(20).

To a solution of(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine,12a, (0.013 g, 0.036 mmol) in mixture of pyridine/CH₂Cl₂ (1 mL of 1:1mixture was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). Thereaction mixture was stirred at 40° C. for 12 h. The solvent wasconcentrated under reduced pressure and the resulting residue waspurified by preparatory HPLC (0.1%TFA-H₂O/acetonitrile) to afford thedesired product, 20.

LCMS RT=3.0 (M+1) 460.4, (M−1) 458.4.

Other analogs that can be prepared in the same manner as 20:

(R)-N-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamide(128)

LCMS RT=3.0 (M+1) 460.4, (M−1) 458.4.

(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(thiophen-3-yl)piperidine-1-carboxamide(22)

LCMS RT=2.9 (M+1) 486.3, (M−1) 484.6.

(S)-ethyl2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamido)ethanoate(25)

LCMS RT=2.6 (M+1) 490.3, (M−1) 488.4.

(S)-ethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonylcarbamate(26)

LCMS RT=2.5 (M+1) 476.3, (M−1) 474.5.

(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-isopropylpiperidine-1-carboxamide(27)

LCMS RT=2.7 (M+1) 446.4, (M−1) 444.5.

(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-methylpiperidine-1-carboxamide(29)

LCMS RT=2.4 (M+1) 418.3, (M−1) 416.1.

(S)-N-allyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamide(39)

LCMS RT=2.6 (M+1) 444.4, (M−1) 442.4.

(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(pyridin-3-yl)piperidine-1-carboxamide(40)

LCMS RT=2.5 (M+1) 481.3, (M−1) 479.4.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(3-fluorophenyl)piperidine-1-carboxamide(75)

LCMS RT=3.0 (M+1) 498.3, (M−1) 496.5.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide(76)

LCMS RT=2.9 (M+1) 510.3, (M−1) 508.5.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(3-ethanoylphenyl)piperidine-1-carboxamide(77)

LCMS RT=2.8 (M+1) 522.3, (M−1) 520.4.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-m-tolylpiperidine-1-carboxamide(78)

LCMS RT=3.0 (M+1) 494.3, (M−1) 492.4.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(3-(trifluoromethyl)phenyl)piperidine-1-carboxamide(79)

LCMS RT=3.3 (M+1) 548.3, (M−1) 546.4.

(R)-ethyl3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamido)propanoate(118)

LCMS RT=2.6 (M+1) 504.2, (M−1) 502.5.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(5-methyl-2-(trifluoromethyl)furan-3-yl)piperidine-1-carboxamide(120)

LCMS RT=3.2 (M+1) 552.4, (M−1) 550.5.

(R)-methyl2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamido)ethanoate(125)

LCMS RT=2.6 (M+1) 490.4, (M−1) 488.6.

(R)-N-tert-butyl-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxamide(117)

LCMS RT=2.8 (M+1) 486.3, (M−1) 484.5.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(thiophen-2-yl)piperidine-1-carboxamide(129)

LCMS RT=2.8 (M+1) 486.3, (M−1) 484.5.

(R)-methyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carbonylcarbamate(131)

LCMS RT=1.6 (M+1) 462.7.

(R)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-(4-methylthiophen-2-yl)piperidine-1-carboxamide(130)

LCMS RT=2.0 (M+1) 500.6.

(S)-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N,N-dimethylpiperidine-1-carboxamide(228)

LCMS RT=2.3 (M+1) 398.3.

(R)-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-methylpiperidine-1-carboxamide(274)

LCMS RT=2.1 (M+1) 384.3.

(R)-N-ethyl-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidine-1-carboxamide(275)

LCMS RT=2.2 (M+1) 398.4.

(R)-3-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-propylpiperidine-1-carboxamide(276)

LCMS RT=2.3 (M+1) 412.4.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(methylsulfonyl)-piperidin-3-yl)methyl)pyrimidin-4-amine(36).

To a solution of(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine,12a, (0.018 g, 0.050 mmol) and pyridine (0.7 mL) in CH₂Cl₂ (0.7 mL) wasadded methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reactionmixture was stirred at room temperature for 24 hours. The solvent wasconcentrated under reduced pressure and the resulting residue waspurified by preparatory HPLC (0.1%TFA-H₂O/acetonitrile) to afford thedesired product, 36.

LCMS RT=2.7 (M+1) 439.3, (M−1) 437.3.

Other analogs that can be prepared in the same manner as 36:

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1-(cyclopropylsulfonyl)piperidin-3-yl)methyl)-5-fluoropyrimidin-4-amine(61)

LCMS RT=2.8 (M+1) 465.3, (M−1) 463.3.

(R,E)—2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(styrylsulfonyl)piperidin-3-yl)methyppyrimidin-4-amine(60)

LCMS RT=3.2 (M+1) 525.3.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(3-methoxyphenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(62)

LCMS RT=3.1 (M+1) 531.3, (M−1) 529.4.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(4-fluorophenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(64)

LCMS RT=3.1 (M+1) 519.3, (M−1) 517.4

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(3-fluorophenylsulfonyl)piperidin-3-yl)methyppyrimidin-4-amine(65)

LCMS RT=3.1 (M+1) 519.2, (M−1) 517.4.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(m-tolylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(66)

LCMS RT=3.2 (M+1) 515.3, (M−1) 513.4

(R)-N-((1-(3-bromophenylsulfonyl)piperidin-3-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(67)

LCMS RT=3.3 (M+1) 579.2, (M−1) 577.2.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(phenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(87)

LCMS RT=2.1 (M+1) 501.3.

(R)-N-((1-(3-bromophenylsulfonyl)piperidin-3-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(88)

LCMS RT=2.0 (M+1) 561.3.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(phenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(89)

LCMS RT=2.1 (M+1) 507.2.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(2-fluorophenylsulfonyl)piperidin-3-yl)methyppyrimidin-4-amine(90)

LCMS RT=2.1 (M+1) 519.2.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(1-methyl-1H-imidazol-4-ylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine(91)

LCMS RT=1.8 (M+1) 505.3.

Formation of(S)-3-((S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-methylpropan-1-ol(135).

To a solution of (R)-3-bromo-2-methylpropan-1-ol (0.006 mL, 0.055 mmol)and(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)-pyrimidin-4-amine,12a, (0.020 g, 0.055 mmol) in CH₃CN (2 mL) was added K₂CO₃ (0.023 g,0.165 mmol). The reaction mixture was heated at 80° C. at for 24 h. Thesolvent was concentrated under reduced pressure and the resultingresidue was purified by preparatory HPLC (0.1%TFA-H₂O/acetonitrile) toafford the desired product, 135.

LCMS RT=2.5 (M+1) 433.4, (M−1) 431.6.

Other analogs that can be prepared in the same manner as 135:

(S)-1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3,3-dimethylbutan-2-one(140)

LCMS RT=2.9 (M+1) 459.3, (M−1) 457.5.

(R)-3-((S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-methylpropan-1-ol(141)

LCMS RT=1.4 (M+1) 433.5.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(2-methylbenzyl)piperidin-3-yl)methyppyrimidin-4-amine(139)

LCMS RT=3.2 (M+1) 465.3, (M−1) 463.4.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(3-methylbenzyl)piperidin-3-yl)methyppyrimidin-4-amine(137)

LCMS RT=3.1 (M+1) 465.4, (M−1) 463.6.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1-(cyclohexylmethyl)piperidin-3-yl)methyl)-5-fluoropyrimidin-4-amine(134)

LCMS RT=3.1 (M+1) 457.3, (M−1) 455.5.

(S)-2-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-ypethanol(133)

LCMS RT=2.3 (M+1) 405.3, (M−1) 403.6.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1-(2,2-dimethoxyethyl)piperidin-3-yl)methyl)-5-fluoropyrimidin-4-amine(132)

LCMS RT=2.2 (M+1) 449.7.

(S,E)-methyl4-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)but-2-enoate(138)

LCMS RT=2.8 (M+1) 459.3, (M−1) 457.7.

(S)-4-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)butanenitrile(666)

LCMS RT=2.6 (M+1) 428.3, (M−1) 426.5.

(S)-3-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)propanenitrile(667)

LCMS RT=1.4 (M+1) 414.5.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(pyrimidin-2-yl)piperidin-3-yl)methyl)pyrimidin-4-amine(124)

LCMS RT=3.1 (M+1) 439.3 (M-H) 437.4.

Formation of 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate(13b).

To a cold (5° C.) solution of methyl 4-hydroxypiperidine-2-carboxylate,13a, (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) inCH₂Cl₂ (135 mL) was added dropwise benzyl chloroformate (6.20 mL, 43.43mmol) over 10 min. The resulting solution was stirred at 5° C. for 1hour and then allowed to warm to room temperature. The reaction mixturewas diluted with water and the layers were separated. The aqueous wasre-extracted with CH₂Cl₂ and the combined organics were dried overMgSO₄, filtered and evaporated to dryness. The crude was passed througha plug of silica gel, eluting with 30-80% EtOAc/Hexanes to afford thedesired product, 13b.

¹H NMR (300 MHz, CDCl₃) δ 7.36-7.33 (m, 5H), 5.17 (s, 2H), 4.89-4.78 (m,1H), 4.18-4.09 (m, 1H), 3.96 (s, 1H), 3.76-3.70 (m, 3H), 3.53-3.41 (m,2H), 2.44 (s, 1H), 1.96-1.91 (m, 1H) and 1.71 (s, 2H) ppm.

Formation of 1-benzyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate (13c).

To a 500 ml flask, flamed dry under N₂ was added CH₂Cl₂ (65 mL) followedby oxalyl chloride (5.2 mL, 59.6 mmol). After cooling the reactionmixture to −78° C., dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added,followed by 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate,13b, (8.6 g, 29.2 mmol) in CH₂Cl₂ (65 mL). The reaction was allowed tostir at −78° C. for 45 min. To the mixture was added triethylamine (24.4mL, 175.1 mmol) and the mixture was allowed to warm to room temperature.The reaction mixture was diluted with CH₂Cl₂ and 1N HCl. The layers wereseparated and the aqueous phase was re-extracted with CH₂Cl₂.Thecombined organic phases were washed with water, dried over MgSO₄,filtered and evaporated to dryness. The crude was purified by silica gelchromatography (30-50% EtOAc/hexanes) to give the desired product, 13c.

¹H NMR (300 MHz, CDCl₃) δ 7.37 (s, 5H), 5.24-5.18 (m, 3H), 5.02 (s, 1H),4.12 (q, J=7.1 Hz, 1H), 3.74-3.65 (m, 3H), 2.79 (d, J=7.0 Hz, 2H) and2.53 (s, 2H) ppm.

Formation of 1-benzyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate(13d).

To a cold (0° C.) solution of 1-benzyl 2-methyl4-oxopiperidine-1,2-dicarboxylate, 13c, (7.4 g, 25.4 mmol) in THF (75mL) was added (diethylamino)sulfur trifluoride (25.0 mL, 189.2 mmol).After 2 hours at 0° C., the reaction was quenched by the carefuladdition of water. The mixture was diluted with EtOAc and water. SolidNaHCO₃ was added to adjust the pH to neutral. The layers were separatedand the organic was washed with water, brine, dried over MgSO₄, filteredand evaporated to dryness. The crude was passed through a plug of silicagel eluting with 15-20% EtOAc/hexanes to afford the desired product,13d.

¹H NMR (300 MHz, CDCl₃) δ 7.37-7.31 (m, 5H), 5.30-5.06 (m, 3H),4.45-4.22 (m, 1H), 3.76-3.52 (m, 3H), 3.45 (d, J=9.0 Hz, 1H), 2.76 (s,1H) and 2.23-1.93 (m, 3H) ppm.

Formation of 1-tert-butyl 2-methyl4,4-difluoropiperidine-1,2-dicarboxylate (13e).

To a Parr flask (1 L) was charged 10% palladium on carbon (0.57 g) anddi-tert-butyl dicarbonate (4.47 g, 20.49 mmol). A solution of 1-benzyl2-methyl-4,4-difluoropiperidine-1,2-dicarboxylate, 13d, (4.28 g, 13.66mmol) in methanol (150 mL) was added and hydrogen was introduced viaparr shaker (46 PSI). The reaction mixture was shaken over weekend atroom temperature. The mixture was filtered through Celite and washedthroughly with CH₂Cl₂.The filtrate was concentrated to dryness andredissolved in 10% EtOAc/hexanes. The crude was purified by silica gelchromatography (10-20% EtOAc/hexanes) to afford 5.1 g of a mixture ofdesired product, 13e, plus approximately 840 mg of contaminated product.The resulting crude mixture was used directly in next step withoutfurther purification.

¹H NMR (300 MHz, CDCl₃) δ 5.08 (s, 1H), 4.89 (s, 1H), 4.12 (q, J=7.2 Hz,1H), 3.76 (s, H), 3.74 (s, 3H), 3.34 (s, 1H), 3.29 (t, J=7.2 Hz, 1H),2.77 (s, 1H), 2.04 (m, 1H) and 1.53 (s, 9H) ppm.

Formation of 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylicacid (13f)

To a solution of 1-tert-butyl 2-methyl4,4-difluoropiperidine-1,2-dicarboxylate, 13e, (4.6 g, 16.5 mmol) in THF(18 mL), methanol (18 mL) and H₂O (9 mL) was added lithium hydroxide(3.45 g, 82.22 mmol). The reaction mixture was stirred at roomtemperature for 1 hour. All volatiles were removed under reducedpressure. The residue was diluted with a slight amount of water andether. The layers were separated and the organic phase was discarded.The aqueous phase was acidified to pH 3 with the addition of aqueoussaturated KHSO₄ solution. The product was extracted with EtOAc. Theorganic phase was washed with water, dried over MgSO₄, filtered andevaporated to dryness. The resulting product was used without furtherpurification.

¹H NMR (300 MHz, CDCl₃) δ 5.14 (s, 1H), 4.93 (s, 1H), 4.12 (q, J=7.1 Hz,1H), 3.28 (d, J=6.3 Hz, 1H), 2.75 (d, J=8.7 Hz, 1H), 2.06 (d, J=8.5 Hz,1H), 1.99-1.81 (m, 1H) and 1.47 (s, 9H) ppm.

Formation of tert-butyl 2-carbamoyl-4,4-difluoropiperidine-1-carboxylate(13 g)

To a solution of1-tert-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid, 13f,(1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) was added pyridine (0.35 mL,4.33 mmol), followed by di-tert-butyl dicarbonate (1.78 g, 8.17 mmol)and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure and the residue was taken up in EtOAc. The organicphase was washed with water, aqueous saturated KHSO₄ solution, brine,dried over Na₂SO₄, filtered and evaporated to dryness. The crude residuewas used without further purification.

Formation of tert-butyl 2-cyano-4,4-difluoropiperidine-1-carboxylate(13h)

To a solution of tert-butyl2-carbamoyl-4,4-difluoro-piperidine-1-carboxylate, 13 g, (1.72 g, 6.51mmol) in CH₂Cl₂ (50 mL) was added was N,N-triethylamine (2.03 mL, 14.61mmol) followed by the dropwise addition of(2,2,2-trifluoroacetyl)-2,2,2-trifluoroacetate (1.02 mL, 7.32 mmol).After 15 minutes, the mixture was diluted with aqueous saturated NaHCO₃solution and the layers were separated. The organic phase was washedwith water, dried over Na₂SO₄, filtered and evaporated to dryness. Thecrude residue was passed through a plug of silica gel and eluted with10-30% EtOAc/hexanes to afford the desired product, 13 h.

¹H NMR (300 MHz, CDCl_(⊐)) δ 5.43 (s, 1H), 4.19 (s, 1H), 3.25 (s, 1H),2.36 (m, 1H), 2.23-2.12 (m, 1H), 1.83 (s, 1H), 1.70 (s, 1H) and1.53-1.46 (m, 9H) ppm.

Formation of tert-butyl2-(aminomethyl)-4,4-difluoropiperidine-1-carboxylate (13i)

Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (2×) and chargedinto a parr shaker. A solution of tert-butyl2-cyano-4,4-difluoro-piperidine-1-carboxylate, 13 h, (1.33 g, 5.40 mmol)in methanol (50 mL). The reaction mixture was subject to hydrogenationconditions overnight on the parr shaker (46 PSI). The mixture wasfiltered through celite and washed throughly with CH₂Cl₂. All volatileswere removed at reduced pressure and the crude material was used withoutfurther purification.

Formation of tert-butyl2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate(13j)

To a solution of tert-butyl2-(aminomethyl)-4,4-difluoro-piperidine-1-carboxylate, 13i, (0.10 g,0.41 mmol) and5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(0.18 g, 0.38 mmol) in THF (2 mL) was added ^(i)Pr₂NEt (0.20 mL, 1.15mmol). The reaction mixture was heated in microwave at 130° C. for 15minutes. The reaction was cooled to room temperature and the volatileswere removed under reduced pressure. The crude residue was purified viasilica gel chromatography (0-100% EtOAc/hexanes) to afford the desiredproduct, 13j.

LCMS (M−1) 649.52.

Formation of tert-butyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate(13k).

To a solution of tert-butyl2-[[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]methyl]-4,4-difluoro-piperidine-1-carboxylate,13j, (0.23 g, 0.35 mmol) in methanol (4 mL) was added sodium methanolate(4 mL of 25% w/v, 18.51 mmol). The reaction mixture was allowed to stirat room temperature for 15 minutes. All volatiles were removed atreduced pressure and the residue was quenched with water. EtOAc wasadded and the layers were separated. The organic phase was washed withbrine, dried (MgSO₄), filtered and evaporated to dryness. The cruderesidue was pure enough to be used without further purification.

LCMS (M+1) 497.44, (M−1) 495.52.

Formation of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((4,4-difluoropiperidin-2-yl)methyl)-5-fluoropyrimidin-4-amine(13m)

To a solution of tert-butyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate,13k, (0.09 g, 0.18 mmol) in 2-propanol (2 mL) was added propan-2-olhydrochloride (2 mL of 6 M, 12.00 mmol). After stirring the reactionmixture at room temperature for 17 hours, an additional 1 mL of IPA/H—Clwas added and the reaction mixture was heated at 45° C. for 1 hour. Allvolatiles were removed at reduced pressure and the residue was useddirectly in the next step without further purification.

LCMS (M+1) 397.40, (M−1) 395.44.

Formation of1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidin-1-yl)-3-methoxypropan-1-one(584)

To a solution of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-[(4,4-difluoro-2-piperidyl)methyl]-5-fluoro-pyrimidin-4-amine,13k, (0.086 g, 0.198 mmol) in CH₂ Cl₂ (1 mL), DMF (0.5 mL) and^(i)Pr₂NEt (0.10 mL, 0.57 mmol) was added 3-methoxypropanoyl chloride(2.43 g, 0.20 mmol). The reaction mixture was stirred at roomtemperature for 17 hours. All volatiles were removed at reduced pressureand the residue was purified via silica gel chromatography to give amixture enriched in desired product, 13, which was repurified viapreparatory HPLC.

¹H NMR (300 MHz, d6-DMSO) δ 12.45 (m, 1H), 8.71 (d, J=8.5 Hz, 1H), 8.31(m, 2H), 8.01 (m, 1H), 5.33 (s, 1H), 4.62-4.43 (m, 2H), 4.39-3.72 (m,5H), 3.68 (s, 2H), 3.43-3.40 (m, 1H), 3.15 (s, 1H), 3.07 (s, 1H), 2.33(s, 2H) and 2.08 (s, 2H) ppm: LCMS (M+1) 483.44, (M−1) 481.52.

Other analogs that may be prepared in the same manner as 584 aredescribed below:

N-((4-benzylmorpholin-2-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (388).

¹H NMR (300 MHz, CDCl₃) δ 9.14-9.09 (m, 1H), 8.81-8.71 (m, 1H), 8.29 (d,J=2.3 Hz, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.34 (s, 5H), 5.58-5.41 (m, 1H),3.92-3.43 (m, 4H), 2.83-2.72 (m, 2H), 2.38-2.28 (m, 2H) and 1.62 (m, 2H)ppm.

LCMS RT=1.8 (M+1) 453.4.

2-((2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-isopropylmorpholine-4-carboxamide(446).

LCMS RT=1.7 (M+1) 448.4

Isopropyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxylate(447).

LCMS RT=2.0 (M+1) 449.3

2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((4-(isopropylsulfonyl)morpholin-2-yl)methyppyrimidin-4-amine(448).

LCMS RT=1.9 (M+1) 469.3

1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)propan-1-one(449).

LCMS RT=1.7 (M+1) 419.4

(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)(cyclopropyl)methanone(450).

LCMS RT=1.7 (M+1) 431.4

tert-Butyl 3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxylate(515).

¹H NMR (300 MHz, CDCl₃) δ 10.38 (s, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.49(d, J=2.3 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J=3.4 Hz, 1H), 6.11 (d, J=5.0Hz, 1H), 4.44 (d, J=9.4 Hz, 1H), 4.02-3.62 (m, 6H), 3.55 (dd, J=2.4,12.1 Hz, 1H), 3.35-3.27 (m, 1H) and 1.40-1.22 (m, 9H) ppm.

LCMS RT=2.5 (M+1) 463.5.

1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)propan-1-one(516).

LCMS RT=1.9 (M+1) 419.4

3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-propylmorpholine-4-carboxamide(517).

¹H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.46(s, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.26 (d, J=3.9 Hz, 1H), 8.08 (d, J=7.5Hz, 1H), 6.30 (s, 1H), 4.28 (s, 1H), 3.93-3.74 (m, 3H), 3.51-3.47 (m,2H), 3.39-3.20 (m, 2H), 2.95 (dd, J=6.2, 13.1 Hz, 3H), 1.35-1.25 (m, 2H)and 0.76 (t, J=7.3 Hz, 3H) ppm.

LCMS RT=2.3 (M+1) 448.54.

Methyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxylate(526).

LCMS RT=2.4 (M+1) 421.0.

Ethyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxylate(527).

LCMS RT=2.5 (M+1) 435.1.

Allyl3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxylate(528).

LCMS RT=2.6 (M+1) 447.1.

1-(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)-2-methylpropan-1-one(529).

LCMS RT=2.5 (M+1) 433.1.

1-(3-((2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)-2,2-dimethylpropan-1-one(530).

LCMS RT=1.9 (M+1) 447.1.

(3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)(cyclobutyl)methanone(531).

LCMS RT=2.6 (M+1) 445.1.

2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((4-(methylsulfonyl)morpholin-3-yl)methyppyrimidin-4-amine(532).

LCMS RT=2.4 (M+1) 441.0.

2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((4-(cyclopropylsulfonyl)morpholin-3-yl)methyl)-5-fluoropyrimidin-4-amine(533).

LCMS RT=2.4 (M+1) 467.0.

3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxamide(534).

LCMS RT=2.0 (M+1) 406.0.

3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-ethylmorpholine-4-carboxamide(535).

LCMS RT=2.2 (M+1) 434.1.

3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-N-isopropylmorpholine-4-carboxamide(536).

LCMS RT=2.3 (M+1) 448.1.

(R)-2-fluoroethyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(180).

LCMS RT=2.1 (M+1) 451.4.

(S)-2-methoxyethyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(161).

LCMS RT=2.8 (M+1) 463.4.

(S)-2-chloroethyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(163).

LCMS RT=3.1 (M+1) 467.4.

(S)-prop-2-ynyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(164).

LCMS RT=3.0 (M+1) 443.5.

(S)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(thiazol-2-yl)methanone(165).

LCMS RT=2.8 (M+1) 472.5.

(S)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone(174).

LCMS RT=2.8 (M+1) 495.6.

(S)-methyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(166).

LCMS RT=2.9 (M+1) 419.5.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-ypethanone(179).

LCMS RT=2.5 (M+1) 403.4.

(S)-ethyl2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-tluoropyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(171).

LCMS RT=3.0 (M+1) 433.3.

(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone(184).

LCMS RT=2.7 (M+1) 495.5.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)propan-1-one(208).

LCMS RT=1.9 (M+1) 417.2.

(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone(190).

LCMS RT=2.9 (M+1) 495.4.

(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(4-tluorophenyl)methanone(209).

LCMS RT=2.0 (M+1) 483.1.

(R)-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)(3-(trifluoromethyl)phenyl)methanone(210).

LCMS RT=2.2 (M+1) 533.1.

(R)-4-chloro-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)butan-1-one(278).

LCMS RT=2.4 (M+1) 465.1.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)pent-4-en-1-one(279).

LCMS RT=2.1 (M+1) 443.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3,3,3-trifluoropropan-1-one(280).

LCMS RT=2.1 (M+1) 471.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)hex—S—yn-1-one(281).

LCMS (M+1) 454.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-3-phenylpropan-1-one(293).

LCMS RT=3.1 (M+1) 493.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)-2-cyclohexylethanone(294).

LCMS RT=3.3 (M+1) 485.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)butan-1-one(295).

LCMS RT=2.9 (M+1) 431.2.

(R)-1-(2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-1-yl)pentan-1-one(326).

LCMS RT=3.0 (M+1) 445.2.

(S)-1-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)ethanone(256).

LCMS RT=2.2 (M+1) 369.3.

(S)-1-(2-45-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)propan-1-one(257).

LCMS RT=2.3(M+1) 383.3.

(S)-1-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)butan-1-one(258).

LCMS RT=2.5(M+1) 397.3.

(S)-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)(phenyl)methanone(259).

LCMS RT=2.4 (M+1) 431.3.

(S)-(2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone(260).

LCMS RT=2.4 (M+1) 461.3.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(methylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine(381).

LCMS RT=2.7 min, (M+H) 439.3

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(ethylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine(382).

LCMS RT=2.9 min, (M+H) 453.3.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(propylsulfonyl)piperidin-2-yl)methyl)pyrimidin-4-amine(328).

LCMS RT=2.2 min, (M+H) 467.1.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(2,2,2-trifluoro-ethylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine(383).

LCMS RT=3.0 min, (M+H) 507.3.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(methylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine(384).

LCMS RT=2.7 min, (M+H) 439.3.

(R)-N-((1-(butylsulfonyl)piperidin-2-yl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(329).

LCMS RT=2.3 min, (M+H) 481.2.

(S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1-(cyclopropylsulfonyl)-piperidin-2-yl)methyppyrimidin-4-amine(386).

LCMS RT=2.9 min, (M+H) 465.3.

(R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1-(3-chloropropylsulfonyl)piperidin-2-yl)methyl)-5-fluoropyrimidin-4-amine(330).

LCMS RT=2.2 min, (M+H) 501.1.

(R)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-isopropylpiperidine-1-carboxamide(371).

LCMS RT=1.8 min, (M+H) 412.2.

(R)-N-cyclopropyl-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-methyl)piperidine-1-carboxamide(372).

LCMS RT=1.9 min, (M+H) 424.2.

(R)-N-ethyl-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-methyl)piperidine-1-carboxamide(373).

LCMS RT=1.7 min, (M+H) 398.2.

(R)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-methylpiperidine-1-carboxamide(374).

LCMS RT=1.6 min, (M+H) 384.2.

(R)-2-((5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-propylpiperidine-1-carboxamide(375).

LCMS RT=1.8 min, (M+H) 412.2.

Formation of1-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol (14a).

To a solution of 2-(aminomethyl)cyclohexanol hydrochloride (0.09 g, 0.54mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.10 g, 0.60 mmol) inisopropanol (2 mL) was added ^(i)Pr₂NEt (0.21 mL, 1.20 mmol). Thereaction mixture was heated at 80° C. for 12 hours. The reaction mixturewas was concentrated under reduced pressure and the resulting residuewas purified by silica gel chromatography (25%-75% EtOAc/hexanes) toafford desired product, 14a.

LCMS (M+1) 260.1, (M−1) 258.3.

Formation of2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol(14b)

To a degassed solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.15 g, 0.35 mmol),1-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14a, (0.09g, 0.35 mmol) and aqueous KOAc solution (1.04 mL of 1M solution, 1.04mmol) in dimethylacetamide was added palladium triphenylphosphine (0.04g, 0.03 mmol). The reaction mixture was heated at 140° C. in microwavefor 15 min and then cooled to room temperature. The reaction mixture wasfiltered through celite, concentrated in vacuo, and the resulting cruderesidue was purified by by preparatory HPLC (0.1%TFA-H₂O/acetonitrile)to afford the desired product, 14b.

LCMS RT=2.6 (M+1) 530.3.

Formation of(2R)-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol(12)

To a solution of2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol,14b, (0.10 g, 0.19 mmol) in THF (3 mL) was added aqueous lithiumhydroxide (1 mL of 1N solution). The reaction mixture was stirred atroom temperature for 12 hours. The resulting residue was purified bypreparatory HPLC (0.1%TFA-H₂O/acetonitrile) to afford the desiredproduct, 12.

LCMS FIA RT=1.9 (M+1) 376.2.

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol(13)

LCMS FIA RT=1.8 (M+1) 362.2.

2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclopentanol(14)

LCMS FIA RT=1.0 (M+1) 348.3.

(1R, 2S, 3R,5R)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-5-(hydroxymethyl)cyclopentane-1,2-diol(657)

¹H NMR (300 MHz, DMSO) δ 12.41 (s, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.28 (d,J=2.4 Hz, 1H), 8.25 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.64 (s, 1H),4.80-4.50 (m, 3H), 4.47 (dd, J=7.5, 14.8 Hz, 1H), 3.89 (dd, J=5.3, 6.3Hz, 1H), 3.77 (dd, J=5.1, 5.0 Hz, 1H), 3.50-3.37 (m, 2H), 2.36-2.24 (m,1H), 2.04 (dd, J=8.3, 13.5 Hz, 1H), 1.99 (s, 1H), 1.27 (td, J=8.4, 4.4Hz, 1H) and 1.21 (s, 1H) ppm.

LCMS RT=3.0 (M+1) 399.4.

Formation of tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (14d)

A solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Niin absolute EtOH was stirred under H₂ atmosphere (50 PSI) for 24 hours.Filtration and evaporation of the solvent followed by flashchromatography (SiO₂, 0-20% MeOH-CH₂Cl₂, gradient elution) provided thetarget compound, 14d, as a racemic mixture of trans isomers (286 mg, 66%yield): FIA (M+H) 229.33.

Formation of tent-butyltrans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl-amino)methyl)cyclohexylcarbamate(14e)

A mixture of5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,15a, (0.42 g, 0.90 mmol) and tert-butyl trans-2-(aminomethyl)cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to70° C. After 1.3 hours, the mixture was concentrated in vacuo. Flashchromatography (SiO₂, 0-60% EA/Hex, gradient elution) provided thedesired intermediate, tert-butyltrans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate,14e, as a racemic mixture of trans isomers, which was taken into thenext reaction without further purification (0.52g , 92% yield).

Formation ofN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(14f)

A solution of the tert-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate,14e, (0.52 g) in CH₂Cl₂ (5 mL) was treated with TFA (2.5 mL) for 30 min.the solution was concentrated in vacuo and the resulting crude materialwas taken up in CH₃CN and concentrated in vacuo several times to removeexcess TFA and to provide the desired amine, 14f, as racemic mixture oftrans isomers, as the TFA salt, which was sufficiently pure for use inthe next reaction.

LCMS RT=1.93 min, (M+H) 529.0

Formation ofN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(555)

A solution ofN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, (0.050 g, 0.077mmol) in THF was treated with LiOH (0.5 mL, 1.0M) at 60° C. After 5 min,at 120° C., the solution was diluted with EtOAc, and washed with brine,filtered and concentrated in vacuo. Preparative HPLC provided thedesired compound, 555, as a racemic mixture of trans isomers (12 mg, 33%yield).

¹H NMR (300 MHz, MeOD) δ 8.75 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H),8.29 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 3.96 (dd, J=5.8, 14.4 Hz, 1H),3.73 (dd, J=4.3, 14.3 Hz, 1H), 3.08-3.00 (m, 1H), 2.05-1.87 (m, 3H),1.80 (m, 3H) and 1.48-1.39 (m, 4H) ppm;

LCMS RT=1.9 min, (M+H) 375.0.

Formation ofN-(trans-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexyl)-2-methoxyethanamide(556)

To a cooled mixture ofN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(0.060 g, 0.093 mmol) and ^(i)Pr₂NEt (0.057 mL, 0.330 mmol) in CH₂Cl₂(2mL) at 0° C., was added 2-methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room temperature.After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120° C. for 10min. The resulting mixture was cooled to room temperature andpartitioned and the aqueous layer extracted with EtOAc and the combinedorganics were concentrated in vacuo. Preparative HPLC provided thedesired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17%yield).

¹H NMR (300 MHz, MeOD) δ 8.74 (d, J=2.3 Hz, 1H), 8.42 (s, 1H), 8.38 (d,J=2.3 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 3.85-3.81 (m, 2H), 3.75 (d, J=8.5Hz, 2H), 3.26 (s, 3H), 1.97-1.77 (m, 5H) and 1.43-1.35 (m, 4H) ppm; LCMSRT=2.8 min, (M+H) 446.8.

The following analogs can be prepared in same manner as 556.

Formation ofN-(trans-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexyl)methanesulfonamide(557)

Sulfonamide 557 was prepared according to the procedure for compound 36(Scheme 12B) usingN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine,14f, and methane sulfonyl chloride, afforded desired product, 557, as aracemic mixture of trans isomers.

¹H NMR (300.0 MHz, MeOD) δ 8.78 (d, J=2.4 Hz, 1H), 8.45 (d, J=4.2 Hz,1H), 8.37 (d, J=2.3 Hz, 1H), 8.26 (d, J=5.4 Hz, 1H), 4.12 (dd, J=4.5,13.7 Hz, 1H), 3.89 (dd, J=7.1, 13.8 Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s,3H), 2.18-1.90 (m, 2H), 1.79-1.74 (m, 2H) and 1.50-1.25 (m, 4H) ppm;LCMS RT=2.8 min, (M+H) 452.6.

Formation of3-(trans-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexyl)-1,1-dimethylurea(564)

Urea 564 was prepared according to the procedure for compound 20 (Scheme12A) usingN-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine,14f, and dimethylcarbomoyl chloride, afforded desired product, 564, as aracemic mixture of trans isomers.

¹H NMR (300.0 MHz, MeOD) δ 8.78 (d, J=2.4 Hz, 1H), 8.45 (d, J=4.2 Hz,1H), 8.37 (d, J=2.3 Hz, 1H), 8.26 (d, J=5.4 Hz, 1H), 4.12 (dd, J=4.5,13.7 Hz, 1H), 3.89 (dd, J=7.1, 13.8 Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s,3H), 2.18-1.90 (m, 2H), 1.79-1.74 (m, 2H) and 1.50-1.25 (m, 4H) ppm;LCMS RT=1.9 min, (M+H) 445.7.

Formation of (1S,2S)-N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine(15b)

5Chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,15a, (0.25 g, 0.53 mmol) and (1S,2S)-cyclohexane-1,2-diamine (0.12 g,1.08 mmol) were dissolved in THF (3.0 mL), and heated to 140° C. for 20minutes in a sealed vial. The solvent was evaporated in vacuo and theresidue was purified by silica gel chromatography (0%-15% MeOH/CH₂Cl₂)to provide product, 15b, as a white foamy solid (220 mg, 79% yield).

¹H NMR (300 MHz, CDCl₃) δ 8.85 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (d,J=2.4 Hz, 1H), 8.13-8.09 (m, 3H), 7.31-7.28 (m, 2H), 5.14 (d, J=6.6 Hz,1H), 3.96-3.85 (m, 1H), 2.69 (td, J=10.2, 4.7 Hz, 1H), 2.40 (s, 3H),2.33 (d, J=5.6 Hz, 1H), 2.12-2.06 (m, 1H), 1.88-1.84 (m, 2H) and1.60-1.21 (m, 4H) ppm; LCMS RT=2.33 (M+1) 515.2.

Formation of N-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide(433).

(1S,2S)-N-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,2-diamine,15b, (0.100 g, 0.194 mmol) was dissolved in dichloromethane (2 mL) andtreated with ^(i)Pr₂NEt (0.075 g, 0.101 mL, 0.583 mmol). Acetyl chloride(0.021 mL, 0.291 mmol) was added and the reaction was allowed to stir atroom temperature for 30 minutes. The volatiles were evaporated underreduced pressure, and the residue was dissolved in dichloroethane (2 mL)and treated with LiOH (0.097 mL of 1 M solution, 0.971 mmol). Thereaction mixture was heated in the microwave at 150° C. for 10 minutes.The reaction was diluted with EtOAc (5 mL) and water (5 mL) and thelayers were separated. The aqueous layer was extracted with EtOAc (2×5mL), and the combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo to provide the crude product, which was purifiedby silica gel chromatography (0%-15% MeOH/CH₂Cl₂) to provide N-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide,433, (34 mg, 44% yield).

¹H NMR (300 MHz, d6-DMSO) δ 13.03 (s, 1H), 9.10 (s, 1H), 9.05 (s, 1H),8.67 (d, J=2.1 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H), 8.43 (d, J=2.3 Hz, 1H),7.97 (d, J=7.7 Hz, 1H), 4.15-4.07 (m, 1H), 3.93-3.87 (m, 1H), 2.20-2.15(m, 1H), 1.99-1.92 (m, 1H), 1.85-1.79 (m, 2H), 1.74 (s, 3H) and1.52-1.36 (m, 4H) ppm; LCMS RT=2.41 (M+1) 403.4.

Formation ofN1-(2-chloro-5-fluoropyrimidin-4-yl)cyclohexane-cis-1,2-diamine (16a)2,4-Dichloro-5-fluoropyrimidine (0.50 g, 2.99 mmol) was dissolved inisopropanol (7 mL) and treated with ^(i)Pr₂NEt (1.50 mL, 8.98 mmol).Cyclohexane-cis-1,2-diamine (0.46 g, 4.03 mmol) was added and thereaction was allowed to stir at room temperature overnight. The solventwas evaporated and the reaction mixture was diluted in EtOAc (15 mL) andwashed with aqueous saturated NaHCO₃ solution. The aqueous layer wasextracted with EtOAc (15 mL) and the combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to provide the crude product. Theresulting crude was purified by silica gel chromatography (5%-30%MeOH/CH₂Cl₂) to provide 16a (370 mg, 50% yield) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=2.8 Hz, 1H), 6.16 (s, 1H), 4.08 (s,1H), 3.13 (d, J=3.9 Hz, 1H) and 1.84-1.44 (m, 8H) ppm; LCMS RT=0.8 (M+1)245.1.

Formation ofN1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine(16b)

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(0.26 g, 0.65 mmol) was dissolved in DME (8 mL) and treated withN1-(2-chloro-5-fluoropyrimidin- 4-yl)cyclohexane-cis-1,2-diamine, 16a,(0.16 g, 0.65 mmol). Pd(PPh₃)₄ (0.10 mg, 0.08 mmol) and 2M aqueousNa₂CO₃ (3.25 mL) were added and the suspension was heated in themicrowave to 150° C. for 20 minutes. 1M aqueous LiOH (5 mL) was added,and the reaction was heated in the microwave to 150° C. for anadditional 15 minutes. The organic solvent was evaporated under reducedpressure and the aqueous phase was extracted with CH₂Cl₂ (2×20 mL). Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuo. The resulting residue was purified by silica gel chromatography(0%-100% CH₂Cl₂/EtOAc) to provide product 16b (140 mg, 66% yield) as abrown foam.

¹H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H), 8.66 (d, J=8.0 Hz, 1H),8.29-8.22 (m, 3H), 7.81 (s, 2H), 7.28-7.19 (m, 2H), 4.55 (s, 1H), 3.74(s, 1H) and 1.92-1.49 (m, 8H) ppm; LCMS RT=1.8 (M+1) 327.2.

Formation ofN-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]methanesulfonamide(337)

N1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine,16b, (0.009 g, 0.027 mmol) was dissolved in an 8:2 mixture of CH₂Cl₂/DMF(1 mL) and treated with ^(i)Pr₂NEt (0.019 mL, 0.110 mmol) andmethanesulfonyl chloride (0.006 mL, 0.083 mmol). The reaction wasstirred at room temperature overnight, concentrated in vacuo and theresidue was purified by HPLC with 10%-90% acetonitrile/water with 0.03%TFA to provide compound 337.

¹H NMR (300 MHz, d6-DMSO) δ 12.47 (s, 1H), 8.64 (d, J=7.8 Hz, 1H),8.45-8.34 (m, 3H), 7.29 (dd, J=4.8, 7.8 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H),4.47-4.25 (m, 1H), 4.05-3.89 (m, 1H), 2.80 (s, 3H), 1.95-1.62 (m, 6H)and 1.49-1.24 (m, 2H) ppm.; LCMS RT=2.3 (M+1) 405.3.

The following compounds can be prepared in a manner similar to the onedescribed in either Scheme 15 or Scheme 16:

N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-cyclohexyl]propanamide(341)

¹H NMR (300 MHz, d6-DMSO) δ 12.47 (s, 1H), 8.65 (d, J=8.1 Hz, 1H),8.49-8.23 (m, 3H), 7.61 (d, J=7.8 Hz, 1H), 7.29 (dd, J=4 .7 , 8.0 Hz,1H), 4.39 (d, J=19.5 Hz, 2H), 2.10 (q, J=7.6 Hz, 2H), 1.79-1.64 (m, 6H),1.48 (d, J=6.4 Hz, 2H) and 0.91 (t, J=7.6 Hz, 3H) ppm; LCMS RT=2.3 (M+1)383.4.

N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]butanamide(342)

LCMS RT=2.5 (M+1) 397.4.

N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide(343)

LCMS RT=2.7 (M+1) 423.4.

N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]benzamide(344)

LCMS RT=2.7 (M+1) 431.4.

N-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]propane-1-sulfonamide(346)

¹H NMR (300 MHz, d6-DMSO) δ 12.41 (s, 1H), 8.65 (d, J=7.8 Hz, 1H),8.38-8.33 (m, 3H), 7.28 (dd, J=4.7, 7.9 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H),4.36 (s, 1H), 3.88 (s, 1H), 2.83 (t, J=7.7 Hz, 2H), 1.85-1.70 (m, 6H),1.59 (q, J=7.8 Hz, 2H), 1.47-1.24 (m, 2H) and 0.82 (t, J=7.4 Hz, 3H)ppm; LCMS RT=2.6 (M+1) 433.3.

1-[cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea(347)

¹H NMR (300 MHz, d6-DMSO) δ 12.47 (s, 1H), 8.64 (d, J=7.8 Hz, 1H),8.45-8.34 (m, 3H), 7.29 (dd, J=4.8, 7.8 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H),4.47-4.25 (m, 1H), 4.05-3.89 (m, 1H), 2.80 (s, 3H), 1.95-1.62 (m, 6H)and 1.49-1.24 (m, 2H) ppm; LCMS RT=2.4 (M+1) 412.4.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]acetamide (348)

¹H NMR (300 MHz, d6-DMSO) δ 12.53 (s, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.43(s, 1H), 8.39-8.36 (m, 2H), 7.91 (d, J=7.9 Hz, 1H), 7.32 (dd, J=4 .7 ,7.9 Hz, 1H), 4.08-3.94 (m, 1H), 3.86 (d, J=8.4 Hz, 1H), 2.13 (d, J=24.3Hz, 1H), 1.95 (d, J=10.2 Hz, 1H), 1.81-1.73 (m, 2H), 1.73 (s, 3H) and1.43-1.14 (m, 4H) ppm; LCMS RT=2.2 (M+1) 369.4.

N-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propanamide(349)

LCMS RT=2.7 (M+1) 417.3 .

N-[(1R,2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide(351)

LCMS RT=3.1 (M+1) 457.3.

N-[(1R,2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]benzamide(352)

LCMS RT=3.0 (M+1) 465.3.

N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]methanesulfonamide(353)

LCMS RT=2.7 (M+1) 439.4.

N-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-1-sulfonamide(354)

LCMS RT=3.0 (M+1) 467.3 .

1-[(1R, 2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea(355)

LCMS RT=2.8 (M+1) 446.3.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]butanamide (358)

LCMS RT=2.5 (M+1) 397.4.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide(359)

LCMS RT=2.7 (M+1) 423.4.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]benzamide (360)

LCMS RT=2.63 (M+1) 431.4.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]methanesulfonamide(361)

¹H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.66 (d, J=8.0 Hz, 1H),8.43-8.36 (m, 3H), 7.32 (dd, J=4.7, 7.9 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H),4.16 (d, J=9.3 Hz, 1H), 3.35 (d, J=9.8 Hz, 1H), 2.91 (d, J=8.9 Hz, 3H),2.12-2.02 (m, 2H), 1.79-1.73 (m, 2H) and 1.64-1.15 (m, 4H) ppm; LCMSRT=2.4 (M+1) 405.3.

N-[(1R,2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]propane-1-sulfonamide(362)

¹H NMR (300 MHz, d6-DMSO) δ 12.43 (s, 1H), 8.68 (d, J=7.9 Hz, 1H),8.38-8.33 (m, 3H), 7.29 (dd, J=4.7, 7.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H),4.14 (d, J=6.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.07-2.89 (m, 2H), 2.07 (d,J=12.6 Hz, 2H), 1.76 (d, J=7.9 Hz, 2H), 1.61-1.33 (m, 6H) and 0.90 (t,J=7.4 Hz, 3H) ppm; LCMS RT=2.6 (M+1) 433.3.

N-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]butanamide(363)

LCMS RT=2.9 (M+1) 431.3.

N-[(trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide(364)

LCMS RT=3.1 (M+1) 457.3.

N-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]benzamide(365)

LCMS RT=3.0 (M+1) 465.3.

N-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-1-sulfonamide(367)

LCMS RT=3.0 (M+1) 467.3.

1-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea(368)

LCMS RT=2.8 (M+1) 446.3.

Methyl N-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(425)

¹H NMR (300 MHz, d6-DMSO) δ 13.02 (s, 1H), 9.10 (s, 2H), 8.67 (s, 1H),8.44-8.40 (m, 2H), 7.26 (d, J=6.5 Hz, 1H), 4.19 (s, 1H), 3.66 (d, J=9.8Hz, 1H), 3.48 (s, 3H), 2.13 (s, 1H), 2.02 (d, J=9.2 Hz, 1H), 1.78 (d,J=9.6 Hz, 2H) and 1.47-1.34 (m, 4H) ppm;

LCMS RT=2.1 (M+1) 419.2.

1-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-urea(426)

¹H NMR (300 MHz, d6-DMSO) δ 12.56 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.35(dd, J=2.4, 6.8 Hz, 2H), 8.28 (d, J=4.2 Hz, 1H), 5.99 (d, J=7.0 Hz, 1H),5.80-5.63 (m, 1H), 3.91-3.87 (m, 1H), 3.66-3.45 (m, 1H), 2.54 (s, 3H),2.30 (d, J=13.0 Hz, 1H), 2.04 (d, J=46.9 Hz, 1H), 1.78 (d, J=8.5 Hz, 2H)and 1.56-1.23 (m, 4H) ppm; LCMS RT=2.5 (M+1) 419.5.

3-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(427)

¹H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.41(d, J=2.7 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 8.29 (d, J=4.4 Hz, 1H), 8.23(s, 1H), 6.19 (d, J=7.8 Hz, 1H), 4.04-3.97 (m, 1H), 3.78-3.69 (m, 1H),2.68 (s, 6H), 2.31 (d, J=11.6 Hz, 1H), 1.95 (d, J=9.8 Hz, 1H), 1.79 (d,J=10.4 Hz, 2H) and 1.60-1.32 (m, 4H) ppm; LCMS RT=2.7 (M+1) 432.4.

N-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]methanesulfonamide(428)

¹H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.72 (d, J=2.3 Hz, 1H),8.38-8.29 (m, 3H), 7.82 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 4.52 (brs, 1H),4.12-4.05 (m, 1H), 2.92 (s, 3H), 2.09 (d, J=12.8 Hz, 2H), 1.78 (brs, 2H)and 1.49-1.39 (m, 4H) ppm; LCMS RT=2.7 (M+1) 439.4.

1-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-urea(430)

¹H NMR (300 MHz, d6-DMSO) δ 12.61 (s, 1H), 8.68 (d, J=2.2 Hz, 1H),8.39-8.31 (m, 4H), 6.12 (d, J=6.7 Hz, 1H), 5.91-5.83 (m, 1H), 4.29-4.13(m, 1H), 4.02-3.91 (m, 1H), 2.55 (s, 3H), 1.93 (d, J=12.8 Hz, 1H) and1.74-1.53 (m, 7H) ppm; LCMS RT=2.6 (M+1) 418.5.

3-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(431)

¹H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.68 (d, J=2.3 Hz, 1H),8.33-8.29 (m, 3H), 7.96 (s, 1H), 5.72 (d, J=6.9 Hz, 1H), 4.36 (s, 1H),4.10 (s, 1H), 2.76 (s, 6H), 1.96-1.87 (m, 2H), 1.74-1.63 (m, 4H) and1.55-1.45 (m, 2H) ppm; LCMS RT=2.8 (M+1) 432.4.

Methyl N[Icis-2-[[2-(5-chloro-1H-pyrr olo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(432)

¹H NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.67 (d, J=2.2 Hz, 1H),8.35-8.29 (m, 3H), 7.62 (s, 1H), 7.05 (d, J=7.2 Hz, 1H), 4.50-4.40 (m,1H), 4.20-4.10 (m, 1H), 3.46 (s, 3H), 1.87 (d, J=10.9 Hz, 2H), 1.71-1.65(m, 4H) and 1.43 (d, J=7.4 Hz, 2H) ppm;

LCMS RT=2.9 (M+1) 419.4.

N-[5-fluoro-2-(1H-pyrrolo[5,4-b]pyridin-3-yl)pyrimidin-4-yl]cyclohexane-cis-1,2-diamine(206)

LCMS RT=1.9 (M+1) 327.2.

trans-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexanol(207)

LCMS RT=2.2 (M+1) 328.2.

cis-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexanol (277)

LCMS RT=1.6 (M+1) 328.2.

N-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propanamide(333)

LCMS RT=2.7 (M+1) 417.4.

N-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]butanamide(334)

LCMS RT=2.9 (M+1) 431.4.

N-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide(335)

LCMS RT=3.1 (M+1) 457.3.

N-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]benzamide(336)

LCMS RT=3.0 (M+1) 465.4.

N-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-1-sulfonamide(338)

LCMS RT=2.9 (M+1) 467.3.

1-[cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea(339)

LCMS RT=2.9 (M+1) 446.3.

1-[trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea(350)

LCMS RT=2.6 (M+1) 403.3.

N-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]propanamide (356)

LCMS RT=2.3 (M+1) 383.4.

(1R,2R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyppyrimidin-4-yl)cyclohexane-1,2-diamine(31)

LCMS RT=2.2 (M+1) 411.2.

N1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine(4)

LCMS RT=2.2 (M+1) 327.2.

(1R,2R)-N1-(5-chloro-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine(115)

LCMS RT=1.3 (M+1) 377.2.

N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrimidin-4-yl)cyclohexane-1,2-diamine(116)

LCMS RT=3.3 (M+1) 357.2.

N-[(1R,2R)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]butanamide(369)

LCMS RT=2.9 (M+1) 431.3.

1-[(1R, 2R)-2-[[5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea (370)

LCMS RT=2.4 (M+1) 412.4.

2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(2-methoxycyclohexyl)-pyrimidin-4-amine(412)

LCMS RT=3.5 (M+1) 376.4.

Formation of (1S, 3R)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid (18a)

(1S, 3R)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid can be preparedfollowing the literature procedures described in : Barnett, C. J., Gu,R. L., Kobierski, M. E., WO-2002024705, Stereoselective process forpreparing cyclohexyl amine derivatives.

Formation of ethyl (1R,3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate (18b)

(1S, 3R)-3-(Ethoxycarbonyl)cyclohexanecarboxylic acid, 18a, (10.0 g,49.9 mmol) was dissolved in toluene (100 mL) and treated withtriethylamine (7.6 mL, 54.9 mmol) and DPPA (12.2 mL, 54.9 mmol). Theresulting solution was heated to 110° C. and stirred for 1 hour. Aftercooling to 70° C., benzyl alcohol (7.7 mL, 74.9 mmol) was added, and themixture was heated to 85° C. overnight. The resulting solution wascooled to room temperature, poured into EtOAc (150 mL) and water (150mL) and the layers were separated. The aqueous layer was extracted withEtOAc (2×75 mL) and the combined organic extracts were washed with water(100mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo.The crude material was purified by silica gel chromatography (0%-50%EtOAc/hexanes) to provide 18b (15.3 g, containing 25% benzyl alcohol),which was used for the next step without further purification.

Formation of (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylic acid(18c)

Ethyl (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate, 18b, (36g, 117.9 mmol) was dissolved in THF (144.0 mL) and treated with asolution of LiOH (5.647 g, 235.8 mmol) in water (216.0 mL). Afterstirring overnight, the reaction mixture was diluted with water (100mL), washed with methyl tert-butyl ether (150 mL) and brought to pH 3 byaddition of 3N HCl. The acidic solution was extracted with EtOAc (3×100mL), and the combined organic layers were washed with water and brine,dried on Na₂SO₄ and concentrated in vacuo. The crude product wastriturated with methyl tert-butyl ether (30 mL) and filtered to providea first crop of crystals. The filtrate was treated with heptane (20 mL),concentrated to 30 mL and allowed to stand at room temperature for 3hours to provide a second crop of crystals that were collected byfiltration for a total of 14.4 g (44% yield) 18c.

¹H NMR (300 MHz, CDCl₃) δ 7.38-7.33 (m, 5H), 5.11 (s, 2H), 4.68 (s, 1H),3.55 (s, 1H), 2.44 (d, J=11.0 Hz, 1H), 2.32 (d, J=11.7 Hz, 1H),2.03-1.86 (m, 3H) and 1.48-0.88 (m, 4H) ppm.

Formation of benzyl N-[(1S, 3R)-3-carbamoylcyclohexyl]carbamate (18d)

To a solution of (1R, 3S)-3-Benzyloxycarbonylaminocyclohexanecarboxylicacid, 18c, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was addedpyridine (2.9 mL, 36.1 mmol), followed by di-tert-butyl dicarbonate(10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol).After 3 hours, another portion of di-tert-butyl dicarbonate (1.5 g, 6.8mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) was added and stirringwas continued overnight. The reaction was quenched by addition of 2N HCl(400 mL) and stirred for 1 hour. The resulting suspension was filteredunder reduced pressure, washed with 2N HCl (50 mL), water (8×50 mL) andhexanes (3×50 mL) and vacuum dried to provide benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 91%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.40-7.24 (m, 5H), 5.08 (s, 2H), 3.58-3.44 (m,1H), 2.38-2.21 (m, 1H), 2.17 (d, J=12.7, 1H), 2.05-1.78 (m, 8H),1.54-0.97 (m, 5H).

Formation of benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate (18e)

Benzyl N-[(1S, 3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 32.9mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100mL) and treated with . bis(trifluoroacetoxy)iodobenzene (15.5 g, 36.1mmol). The suspension was allowed to stir at room temperature overnightand was then quenched with 1N HCl (100mL). After evaporation of theacetonitrile, the acidic aqueous solution was washed with EtOAc (2×150mL). The pH was adjusted to basic by addition of solid KOH and theresulting emulsion was extracted with EtOAc (3×200 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo toprovide product 18e (6.2 g, 75% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.31-7.45 (m, 5H), 5.11 (s, 2H), 4.90 (br. s.,1H), 3.58 (br. s., 1H), 2.72-2.97 (m, 1H), 2.14 (d, J=11.90 Hz, 1H),1.87-2.02 (m, 1H), 1.73-1.87 (m, 2H), 1.21-1.46 (m, 1H), 0.89-1.18 (m,3H).

Formation of methyl N-[(1R,3S)-3-benzyloxycarbonyl-aminocyclohexyl]carbamate (19a)

Benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate, 18e, (0.99 g, 3.99 mmol)was dissolved in THF (20 mL) and treated with methyl chloroformate (0.62mL, 7.97 mmol), followed by triethylamine (1.67 mL, 11.96 mmol). Afterstirring for 1 hour at room temperature, the solvent was evaporatedunder reduced pressure and the residue was diluted into 1:3 mixture ofCH₂Cl₂: EtOAc (130 mL) and washed with 1N HCl (50 mL) and 2N Na₂CO₃ (50mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to afford the desired product, 19a, as a white solid(1.09g, 89% yield).

¹H NMR (300 MHz, CDCl₃) δ 7.21-7.37 (m, 5H), 5.02 (s, 2H), 4.26-4.62 (m,1H), 3.58 (s, 3H), 3.34-3.54 (m, 2H), 2.24 (d, J=11.71 Hz, 1H),1.82-2.03 (m, 2H), 1.72 (dt, J=3.14, 13.93 Hz, 1H), 1.23-1.44 (m, 1H),0.79-1.02 (m, 3H).

Formation of methyl N-[(1R, 3S)-3-aminocyclohexyl]carbamate (19b)

Methyl N-[(1R, 3S)-3-benzyloxycarbonylaminocyclohexyl]carbamate, 19a,(1.09 g, 3.56 mmol) was dissolved in ethanol (100 mL) and treated with10% Pd/C (0.38 g, 0.36 mmol). The flask was capped, degassed and fittedwith a hydrogen balloon and allowed to stir overnight. The reactionmixture was filtered under nitrogen and concentrated in vacuo to providethe product, 19b, as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 3.31-3.56 (m, 1H), 3.03 (s, 4H), 2.81 (t,J=10.67 Hz, 1H), 2.03-2.20 (m, 1H), 1.71-2.01 (m, 3H), 1.27-1.49 (m,1H), 0.92-1.14 (m, 3H).

Formation of methyl N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(570)

5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine,19b, (2.04 g, 4.39 mmol) and methyl N-[(1R,3S)-3-amino-cyclohexyl]carbamate (0.60 g, 3.14 mmol) were suspended inTHF (16 mL) and heated in the microwave to 130° C. for 20 minutes.Lithium hydroxide (15.67 mL of 1M solution, 15.67 mmol) was added, andthe resulting mixture was heated in the microwave for 20 min at 130° C.The resulting solution was diluted with water (150 mL) and ethyl acetate(200 mL) and the layers were separated. The aqueous layer was extractedwith EtOAc (100 mL) and t organic layers were combined, dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified bysilica gel chromatography (40-100% EtOAc/hexanes) followed by treatmentof the pure fractions with 4N HCl in dioxane to provide thehydrochloride of compound, 570, as an off white solid.

¹H NMR (300 MHz, MeOD) δ 8.81 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H),8.15 (s, 1H), 7.97 (d, J=4.1 Hz, 1H), 4.26-4.18 (m, 1H), 3.71-3.52 (m,1H), 3.59 (s, 3H), 2.36 (d, J=10.5 Hz, 1H), 2.18 (d, J=10.7 Hz, 1H),2.04-1.86 (m, 2H), 1.57 (s, 1H) and 1.43-1.15 (m, 3H) ppm; LCMS RT=2.0(M+1) 419.4 (M−1) 417.3.

Formation of tert-butyl N-[(1R,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(20b)

tert-Butyl N-[(1R, 3S)-3-aminocyclohexyl]carbamate, 20a, (0.15 g, 0.70mmol) and5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,1a, (0.49 g, 1.05 mmol) were dissolved in THF (30 mL) and allowed tostir at room temperature overnight. The solvent was evaporated underreduced pressure and the residue was purified by two rounds of silicagel chromatography - first with (0%-10% MeOH/CH₂Cl₂) second with(10%-50% EtOAc/hexanes) to provide tert-butyl N-[(1R,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(20b) (330 mg, 38%).

¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, J=2.4 Hz, 1H), 8.58 (s, 1H), 8.38 (d,J=2.4 Hz, 1H), 8.13 (s, 1H), 8.09 (t, J=3.3 Hz, 2H), 7.29 (d, J=8.1 Hz,2H), 5.02 (d, J=7.1 Hz, 1H), 4.47 (d, J=7.7 Hz, 1H), 4.25-4.16 (m, 1H),3.68 (d, J=2.0 Hz, 1H), 2.48 (d, J=11.7 Hz, 1H), 2.38 (s, 3H), 2.26 (d,J=12.8 Hz, 1H), 2.11 (d, J=11.9 Hz, 1H), 1.95-1.89 (m, 1H), 1.69-1.56(m, 1H), 1.44 (s, 9H) and 1.28-1.11 (m, 3H) ppm.

Formation of (1R,3S)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine(20c)

tert-Butyl N-[(1S,3R)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate,20b, (0.33 g, 0.53 mmol) was dissolved in CH₂Cl₂ (10 mL) and treatedwith trifluoroacetic acid (2 mL). After stirring for 2 hours, thesolvent was evaporated under reduced pressure and the resulting residuewas passed through a polymer supported carbonate column to provide thefree base of (1R,3S)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.25 g, 0.43 mmol, 81%).

¹H NMR (300 MHz, CDCl₃) δ 8.76 (dd, J=2.4, 6.3 Hz, 1H), 8.52-8.49 (m,1H), 8.39 (d, J=2.4 Hz, 1H), 8.14-8.04 (m, 3H), 7.29 (d, J=7.5 Hz, 2H),5.61 (s, 1H), 4.28-4.16 (m, 1H), 3.19-3.10 (m, 1H), 2.39 (s, 3H),2.39-2.31 (m, 1H), 2.08-1.90 (m, 3H), 1.63-1.50 (m, 1H) and 1.40-1.17(m, 3H) ppm .

Formation of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide(547)

(1R, 3S)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine,20c, (0.050 g, 0.097 mmol) was dissolved in THF (1.0 mL) and treatedwith triethylamine (0.041 mL, 0.290 mmol) and acetyl chloride (0.013 mL,0.190 mmol). After stirring overnight, the solvent was evaporated andthe residue was taken into THF (1.0 mL) and treated with 1M LiOH (1.0mL, 1.0 mmol) . The reaction mixture was heated in the microwave to 130°C. for 10 minutes. The solvent was evaporated under reduced pressure,and the residue was purified by HPLC, using 5%-70% H₂O/acetonitrile with0.1% TFA. The purified fractions were concentrated to dryness to providethe TFA salt of the product, which was dissolved in MeOH and passedthrough a polymer bound carbonate cartridge to provide the free base ofproduct 547.

¹H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99(d, J=4.1, 1H), 4.23 (t, J=11.4, 1H), 3.90 (t, J=11.4, 1H), 2.35 (d,J=11.6, 1H), 2.20 (d, J=12.5, 1H), 2.00 (d, J=15.9, 2H), 1.92 (s, 3H),1.67 (dd, J=26.3, 13.2, 1H), 1.53-1.06 (m, 3H) ppm LCMS RT=2.1 (M+1)403.2.

The following compounds can be prepared by methods similar to thosedescribed in Scheme 19 and Scheme 20:

(1R,3S)-N1-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine(542)

LCMS RT=1.4 (M+1) 361.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide(576)

¹H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99(d, J=4.1, 1H), 4.23 (t, J=11.4, 1H), 3.90 (t, J=11.4, 1H), 2.35 (d,J=11.6, 1H), 2.20 (d, J=12.5, 1H), 2.00 (d, J=15.9, 2H), 1.92 (s, 3H),1.67 (dd, J=26.3, 13.2, 1H), 1.53-1.06 (m, 3H) ppm; LCMS RT=1.8 (M+1)403 (M−1) 401.4.

Methyl N-[(1S,3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(548).

LCMS RT=2.8 (M+1) 419.5.

3-[(1S,3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(549).

LCMS RT=2.6 (M+1) 432.5.

N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-2-methoxy-acetamide(591)

¹H NMR (300 MHz, MeOD) δ 8.82 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H),8.16 (s, 1H), 7.99 (d, J=4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04-3.96 (m,1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, J=11.6 Hz, 1H), 2.21 (d,J=12.5 Hz, 1H), 2.02-1.93 (m, 2H), 1.74-1.62 (m, 1H) and 1.54-1.28 (m,3H) ppm.

LCMS RT=2.6 (M+1) 433.4.

2-methoxyethyl N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(592)

¹H NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99(d, J=3.97 Hz, 1H), 4.18-4.34 (m, 1H), 4.14 (br. s., 2H), 3.49-3.74 (m,3H), 3.3 (s, 3H) 2.38 (d, J=9.06 Hz, 1H), 2.19 (d, J=13.41 Hz, 1H),1.84-2.11 (m, 2H), 1.51-1.78 (m, 1H), 1.12-1.47 (m, 3H) ppm.

LCMS RT=2.5 (M+1) 463.4.

Formation of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-2-carboxamidehydrochloride (638).

To a solution of (1S,3R)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine,20c, (60 mg, 0.12 mmol) in CH₂Cl₂ (3 mL) was addedtetrahydrofuran-2-carboxylic acid (20.3 mg, 0.17 mmol), EDC (26.8 mg,0.14 mmol), HOBt (17.8 mg, 0.12 mmol) and DIPEA (60.2 mg, 0.47 mmol),and the reaction mixture was stirred at room temperature overnight. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in THF (4 mL) and treated with 1M aqueous lithium hydroxide(3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to130° C. for 20 min. The solvent was evaporated under reduced pressure,and the residue was purified by HPLC, using 5-70% MeOH//H₂O with 6 mMHCl over 15 minutes. The purified fractions were concentrated to providethe hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-2-carboxamide,638.

¹H NMR (300 MHz, MeOD) δ 8.55 (d, J=1.0 Hz, 1H), 8.46-8.45 (m, 1H),8.29-8.27 (m, 2H), 4.28 (d, J=6.1 Hz, 2H), 4.00-3.87 (m, 3H), 2.36-2.16(m, 3H), 2.00-1.91 (m, 5H) and 1.75-1.41 (m, 4H) ppm.

LCMS RT=3.77 (M+1) 459.37, (M−1) 457.35.

The following compounds can be prepared by methods similar to thosedescribed in Scheme 19, Scheme 20 and Scheme 21:

(1R,3S)-N1-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine(542)

LCMS RT=1.4 (M+1) 361.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide(576)

¹H NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99(d, J=4.1, 1H), 4.23 (t, J=11.4, 1H), 3.90 (t, J=11.4, 1H), 2.35 (d,J=11.6, 1H), 2.20 (d, J=12.5, 1H), 2.00 (d, J=15.9, 2H), 1.92 (s, 3H),1.67 (dd, J=26.3, 13.2, 1H), 1.53-1.06 (m, 3H) ppm; LCMS RT=1.8 (M+1)403 (M−1) 401.4.

Methyl N-[(1S, 3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(548).

LCMS RT=2.8 (M+1) 419.5.

3-[(1S, 3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(549).

LCMS RT=2.6 (M+1) 432.5.

N-[(1R, 3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-2-methoxy-acetamide(591)

¹H NMR (300 MHz, MeOD) δ 8.82 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H),8.16 (s, 1H), 7.99 (d, J=4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04-3.96 (m,1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, J=11.6 Hz, 1H), 2.21 (d,J=12.5 Hz, 1H), 2.02-1.93 (m, 2H), 1.74-1.62 (m, 1H) and 1.54-1.28 (m,3H) ppm.

LCMS RT=2.6 (M+1) 433.4.

2-methoxyethyl N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate(592)

¹H NMR (300 MHz, MeOD) ≡ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99(d, J=3.97 Hz, 1H), 4.18-4.34 (m, 1H), 4.14 (br. s., 2H), 3.49-3.74 (m,3H), 3.3 (s, 3H) 2.38 (d, J=9.06 Hz, 1H), 2.19 (d, J=13.41 Hz, 1H),1.84-2.11 (m, 2H), 1.51-1.78 (m, 1H), 1.12-1.47 (m, 3H) ppm.

LCMS RT=2.5 (M+1) 463.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-hydroxy-2,2-dimethyl-propanamidehydrochloride (650)

¹H NMR (300 MHz, MeOD) δ 8.56-8.54 (m, 2H), 8.34 (s, 1H), 8.30 (t, J=5.4Hz, 1H), 4.29 (t, J=11.4 Hz, 1H), 3.93 (t, J=11.6 Hz, 1H), 3.54 (s, 2H),2.34 (d, J=10.8 Hz, 1H), 2.18 (d, J=11.4 Hz, 1H), 2.01 (d, J=11.3 Hz,2H), 1.73-1.37 (m, 4H) and 1.15 (s, 6H) ppm.

LCMS RT=3.79 (M+1) 461.38, (M−1) 459.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydropyran-3-carboxamidehydrochloride (633)

¹H NMR (300 MHz, MeOD) δ 8.64 (d, J=2.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d,J=2.2 Hz, 1H), 8.29 (d, J=5.5 Hz, 1H), 4.39 (t, J=11.9 Hz, 1H),3.93-3.82 (m, 3H), 3.54-3.30 (m, 2H), 2.52-2.43 (m, 1H), 2.37-2.33 (m,1H), 2.20 (d, J=11.6 Hz, 1H), 2.01 (d, J=11.3 Hz, 2H), 1.90-1.88 (m,1H), 1.83-1.63 (m, 4H) and 1.59-1.26 (m, 3H) ppm.

LCMS RT=3.25 (M+1) 473.42, (M−1) 471.1.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-hydroxy-propanamidehydrochloride (634)

¹H NMR (300 MHz, MeOD) δ 8.61 (d, J=2.1 Hz, 1H), 8.53 (s, 1H), 8.35 (d,J=2.0 Hz, 1H), 8.29 (d, J=5.5 Hz, 1H), 4.37 (t, J=11.2 Hz, 1H), 3.95 (s,1H), 3.80 (s, 2H), 2.42 (t, J=5.5 Hz, 3H), 2.20 (d, J=11.5 Hz, 1H), 2.03(d, J=11.0 Hz, 2H) and 1.76-1.29 (m, 4H) ppm.

LCMS RT=3.47 (M+1) 433.21, (M−1) 431.3.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-oxetane-3-carboxamidehydrochloride (635)

¹H NMR (300 MHz, MeOD) δ 8.48-8.45 (m, 2H), 8.29-8.23 (m, 2H), 4.84 (d,J=6.0 Hz, 1H), 4.38 (d, J=6.0 Hz, 1H), 4.26-4.23 (m, 1H), 3.96 (s, 1H),3.77-3.62 (m, 2H), 2.36 (s, 1H), 2.18 (d, J=11.5 Hz, 1H), 2.02 (d,J=12.3 Hz, 2H), 1.70-1.25 (m, 4H) and 1.59 (s, 3H) ppm.

LCMS RT=3.12 (M+1) 459.38, (M−1) 457.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydropyran-4-carboxamidehydrochloride (636)

¹H NMR (300 MHz, MeOD) δ 8.64 (d, J=2.3 Hz, 1H), 8.51 (s, 1H), 8.36 (d,J=2.3 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 4.44-4.36 (m, 1H), 3.96-3.87 (m,3H), 3.47-3.37 (m, 2H), 2.49-2.35 (m, 2H), 2.21 (d, J=12.4 Hz, 1H), 2.02(d, J=11.9 Hz, 2H) and 1.83-1.23 (m, 8H) ppm.

LCMS RT=3.12 (M+1) 473.4, (M−1) 471.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-hydroxy-butanamidehydrochloride (640)

¹H NMR (300 MHz, MeOD) δ 8.69 (d, J=2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d,J=2.2 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 4.43 (t, J=11.9 Hz, 1H), 4.14 (q,J=6.1 Hz, 1H), 3.94 (t, J=11.9 Hz, 1H), 2.40-2.19 (m, 4H), 2.03 (d,J=8.2 Hz, 2H), 1.78-1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J=6.1Hz, 3H) ppm.

LCMS RT=3.37 (M+1) 447.41, (M−1) 445.1.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-2-hydroxy-propanamidehydrochloride (642)

¹H NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.39 (d, J=1.5 Hz,1H), 8.31 (d, J=5.3 Hz, 1H), 4.47-4.40 (m, 1H), 4.15 (s, 1H), 3.98 (m,1H), 2.41 (s, 1H), 2.23 (d, J=10.6 Hz, 1H), 2.04 (d, J=11.0 Hz, 2H) and1.77-1.36 (m, 7H) ppm.

LCMS RT=3.52 (M+1) 433.58, (M−1) 431.3.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydropyran-2-carboxamidehydrochloride (651)

¹HNMR (300 MHz, MeOD) δ 8.56-8.51 (m, 2H), 8.33-8.29 (m, 2H), 4.30 (d,J=3.0 Hz, 1H), 3.98 (dd, J=11.5, 23.4 Hz, 2H), 3.83-3.79 (m, 1H), 3.55(t, J=8.9 Hz, 1H), 2.35 (d, J=11.1 Hz, 1H), 2.19 (d, J=11.2 Hz, 1H),2.03-1.90 (m, 4H) and 1.73-1.37 (m, 8H) ppm.

LCMS RT=4.1 (M+1) 473.41, (M−1) 471.4.

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-3-carboxamidehydrochloride (652)

¹H NMR (300 MHz, MeOD) δ 8.72 (d, J=2.3 Hz, 1H), 8.56 (s, 1H), 8.42 (d,J=2.2 Hz, 1H), 8.34 (d, J=5.6 Hz, 1H), 4.51-4.43 (m, 1H), 4.02-3.88 (m,3H), 3.86-3.78 (m, 2H), 3.07-3.02 (m, 1H), 2.42 (d, J=7.5 Hz, 1H), 2.25(d, J=12.0 Hz, 1H), 2.19-2.06 (m, 4H) and 1.79-1.35 (m, 4H) ppm.

LCMS RT=3.9 (M+1) 459.41, (M−1) 457.4.

(S)-tetrahydrofuran-3-yl (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate(649)

LCMS RT=3.3 (M+1) 475.37, (M−1) 473.35.

N-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)-3-methoxypropanamide(611)

LCMS RT=2.0 (M+1) 447.4, (M−1) 445.4.

N-[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]cyclohexane-cis-1,3-diamine(540)

LCMS RT=1.4 (M+1) 361.5.

N-[cis-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexyl]acetamide(452) (prepared from cis/trans 1,3diamino cyclohexane; separated by HPLCfrom trans diastereomer)

LCMS RT=1.3 (M+1) 403.1 (M−1) 401.1.

N-[trans-3-[[2-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamideacetamide (457) (separated by HPLC from cis diastereomer)

LCMS RT=1.6 (M+1) 403.2 (M−1) 401.1.

1-[cis-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-urea(455)

(prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC fromtrans diastereomer)

LCMS RT=1.7 (M+1) 416.2.

1-[trans-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-urea(458)

(prepared from cis/trans 1,3-diamino cyclohexane; separated by HPLC fromcis diastereomer)

LCMS RT=0.8 (M+1) 418.2 (M−1) 416.1.

3-[cis-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(456)

(prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC fromtrans diastereomer)

LCMS RT=1.5 (M+1) 432.2 (M−1) 430.2.

3-[trans-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-1,1-dimethyl-urea(459)

(prepared from cis/trans 1,3diamino cyclohexane; separated by HPLC fromcis diastereomer)

LCMS RT=1.5 (M+1) 432.2 (M−1) 430.2.

Methyl-cis-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexylcarbamate(514) (racemic cis mixture—prepared from cis-1,3-diaminocyclohexane)

LCMS RT=1.3 (M+1) 418.8.

N-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)morpholine-4-carboxamide(647)

LCMS RT=3.6 (M+1) 474.4 (M−1) 472.5.

N-[3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]methanesulfonamide(454)

LCMS RT=1.6 (M+1) 439.1 (M−1) 437.1.

(tetrahydrofuran-3-yl)methyl(1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate(648)

LCMS RT=3.7 (M+1) 489.38, (M−1) 487.49.

Formation N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamidebishydrochloride (637)

To a solution of (1S,3R)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine(0.06 g, 0.12 mmol) in CH₂Cl₂ (3 mL) was added4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol),EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and ^(i)Pr₂NEt (0.06g, 0.47 mmol), and the reaction mixture was stirred at room temperatureovernight. The solvent was evaporated under reduced pressure, and theresidue was dissolved in CH₂Cl₂ (2 mL) and TFA (2 mL) and allowed tostir at room temperature for 2 hours. The resulting solution wasconcentrated in vacuo, dissolved in THF (4mL) and treated with 1Naqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture washeated in the microwave to 130° C. for 20 min. The solvent wasevaporated under reduced pressure, and the residue was purified by HPLC,using 5-70% MeOH/H₂O with 6 mM HC₁ over 15 minutes. The purifiedfractions were concentrated to provide the bis-hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide.

¹H NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.33(d, J=4.7 Hz, 1H), 4.44-4.35 (m, 2H), 4.21 (d, J=12.2 Hz, 1H), 4.04-3.92(m, 2H), 3.58 (d, J=12.3 Hz, 1H), 3.23-3.08 (m, 2H), 2.37 (d, J=8.1 Hz,1H), 2.23 (d, J=11.1 Hz, 1H), 2.05 (d, J=9.7 Hz, 2H), 1.72 (m, 2H) and1.59-1.44 (m, 2H) ppm; LCMS RT=2.4 (M+1) 474.43, (M-1) 472.4.

Other analogs that can be prepared in the same manner as 637 aredescribed below:

N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]piperidine-4-carboxamidebishydrochloride (639)

¹H NMR (300 MHz, MeOD) δ 8.66 (s, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 8.31(d, J=4.7 Hz, 1H), 4.43-4.36 (m, 1H), 3.98-3.91 (m, 1H), 3.43 (d, J=10.3Hz, 2H), 3.03 (t, J=10.6 Hz, 2H), 2.60 (s, 1H), 2.38 (d, J=10.2 Hz, 1H),2.21 (d, J=10.6 Hz, 1H), 2.07-1.92 (m, 6H) and 1.74-1.30 (m, 4H) ppm.

LCMS RT=2.4 (M+1) 472.46, (M−1) 470.4.

Formation of (1S,2S)-N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine(23b)

A solution of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,23a, (0.50 g, 1.08 mmol) in THF (4 mL) was treated with(1S,2S)-cyclohexane-1,2-diamine (0.27 g, 2.37 mmol) and ^(i)Pr₂NEt (2.15mmol) at 120° C. for 10 minutes. The mixture was concentrated in vacuo.The resulting residue was purified by silica gel chromatography (0-20%MeOHCH₂Cl₂) to provide the desired intermediate as a white solid (410mg).

LCMS RT=2.2 (M+1) 515.5.

Formation of methyl (1S,2S)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)cyclohexylcarbamate(23c)

To a mixture of (1s,2S)-N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine,23b, (0.18 g, 0.35 mmol) in dichloromethane (4 mL) at room temperaturewas added ^(i)Pr₂NEt (0.12 mL, 0.70 mmol) followed by methylchloroformate (0.03 mL, 0.37 mmol). After 35 minutes. the mixture wasdiluted with EtOAc, washed successively with aqueous saturated NH₄Cl andaqueous saturated NaHCO₃ and brine, dried over Na₂SO₄ filtered andconcentrated in vacuo to provide the crude product sufficiently pure foruse in the next reaction.

LCMS RT=4.1 (M+1) 573.4.

Formation of (1S,2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N2-methylcyclohexane-1,2-diamine(522)

To a stirred solution of methyl (15,2S)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate,23c, (0.09 g, 0.16 mmol) in THF (3 mL) at room temperature was addedLiA1H₄ (0.06 g, 1.66 mmol) and the mixture was stirred at roomtemperature for additional 2 hours. The reaction was quenched with 0.06mL KOH (5% aq) followed by water (3×0.06 mL). Then, additional Et₂O (6mL) was added and stirring was continued for 20 minutes. The milky whitesuspension was filtered and rinsed with EtOAc and the cake was rinsedwith additional EtOAc. The combined organic phases were concentrated invacuo and purified by preparative HPLC followed by preparative TLC toprovide the desired product as the free base that was then converted tothe HCl salt by treatment with HCl (4N in dioxane).

LCMS RT=1.7 (M+1) 375.5.

Formation of (1S,2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (523)

To a mixture of (1s,2S)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine,23b, (0.08 g, 0.22 mmol) in acetonitrile (1.6 mL) at room temperaturewas added formaldehyde (0.09 mL of 37% w/v, 1.11 mmol) followed byNaCNBH₃ (0.04 g, 0.56 mmol). A gelatinous mix formed and after 4 min themixture became fluid again. After 4 hours, the reaction was quenchedwith 5 mL of 2N NaOH and the mixture was stirred overnight. The mixturewas diluted with EtOAc and stirred until all solid dissolved. The layerwas extracted with EtOAc several times, dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-15% MeOH-CH₂Cl₂)followed by preparatory HPLC provided the desired product, which wasconverted to the corresponding HCl salt with HCl (4N in dioxane).

¹H NMR (300 MHz, MeOD) δ 8.65 (d, J=2.3 Hz, 1H), 8.54 (s, 1H), 8.43 (d,J=5.1 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 4.82-4.72 (m, 1H), 3.66-3.53 (m,1H), 2.96 (s, 3H), 2.77 (s, 3H), 2.33 (d, J=12.3 Hz, 2H), 2.10-1.97 (m,2H) and 1.75-1.48 (m, 4H) ppm; LCMS RT=1.7 (M+1) 389.5.

Formation of 1-[[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol(610)

To a solution of (1S,3R)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine,20c, (50 mg, 0.09 mmol) in methanol (2 mL) was added2-(methoxymethyl)oxirane (9.4 mg, 0.11 mmol) and the reaction mixturewas heated in the microwave to 140° C. for 10 min. 1M aqueous LiOH (1.0mL, 1.0 mmol) was added, and the reaction mixture was heated in themicrowave to 130° C. for 10 min. The solvent was evaporated underreduced pressure, and the residue was purified by HPLC, using 5-70%CH₃CN//H₂O with 0.1% TFA over 15 minutes. The purified fractions wereconcentrated, redisolved in MeOH and passed through a carbonate-PScolumn to provide the free base of the desired product1-[[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol,610.

¹H NMR (300 MHz, MeOD) δ 8.85 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H),8.15 (s, 1H), 7.98 (d, J=4.1 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, J=3.9, 8.2Hz, 1H), 3.55-3.45 (m, 1H), 3.30 (s, 3H), 3.23-3.07 (m, 1H), 2.86-2.77(m, 2H), 2.68-2.59 (m, 1H), 2.44 (d, J=10.9 Hz, 1H), 2.15 (d, J=9.8 Hz,1H), 2.07-1.94 (m, 2H), 1.65-1.56 (m, 1H) and 1.42-1.17 (m, 3H) ppm;LCMS RT=1.52 (M+1) 449.42.

Formation of 2-[[1R,3S)-3-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexylamino]-acetamide(593)

To a solution of (1S,3R)-N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine,20c, (0.050 g, 0.100 mmol) in DMF (2 mL) was added 2-bromoacetamide(0.015 g, 0.100 mmol) and Na₂CO₃ (0.021 g, 0.190 mmol). The reactionmixture was stirred at room temperature overnight. 1M aqueous lithiumhydroxide (2.0 mL, 2.0 mmol) was added, and the reaction mixture washeated in the microwave to 130° C. for 10 min. The solvent wasevaporated under reduced pressure, and the residue was purified by HPLC,using 5-70% CH₃CN//H₂O with 0.1% TFA over 15 minutes. The purifiedfractions were concentrated, redisolved in MeOH and passed through acarbonate-PS column to provide the free base of the desired product2-[[1R,3S)-3-[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexylamino]-acetamide,593.

¹H NMR (300 MHz, MeOD) δ 8.85 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H),8.15 (s, 1H), 7.99 (d, J=4.1 Hz, 1H), 4.28-4.20 (m, 1H), 2.82-2.73 (m,1H), 2.65 (s, 2H), 2.40 (d, J=10.2 Hz, 1H), 2.15 (d, J=8.5 Hz, 1H),2.05-1.92 (m, 2H), 1.64-1.55 (m, 1H) and 1.44-1.12 (m, 3H) ppm; LCMSRT=1.47 (M+1) 418.21.

Formation of(S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol(27a).

To a solution of5-chloro-3-(5-fluoro-4-(methylsulfonyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,1a, (1.09g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) inTHF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heatedat 130° C. in microwave for 10 min. The solvent was removed underreduced pressure and the resulting residue was purified by silica gelchromatography to afford 550 mg of the desired product, 27a.

¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 8.56 (s, 1H), 8.40 (d, J=2.4 Hz,1H), 8.12-8.07 (m, 3H), 7.32-7.28 (m, 2H), 5.70 (m, 1H), 4.35 (m, 1H),4.10 (m, 1H), 2.40 (s, 3H), 2.32 (d, J=12.3 Hz, 1H), 2.0-1.95 (m, 2H),1.70-1.45 (m 4H).

Formation of2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S)-3-methoxycyclohexyl)pyrimidin-4-amine(27b).

To a suspension of methyl iodide (0.20 g, 0.41 mmol) and3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol,27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol andcalcium sulfate (0.28 g, 2.04(mmol). The reaction mixture was stirred atroom temperature for 18 h. The mixture was filtered through celite andthe resulting filtrate was concentrated in vacuo. The resulting crudemixture was purified by silica gel chromatography to afford 120 mg ofthe desired product, 27b.

¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 8.56 (s, 1H), 8.4 (d, J=2.4 Hz,1H), 8.13-8.06 (m, 3H), 7.30 (d, J=8.7 Hz, 2H), 6.00 (s, 1H), 4.42-4.32(m, 1H), 3.60-3.50 (m, 1H), 3.4 (s, 3H), 2.4 (s, 3H), 2.25 (dd, J=3.4,9.7 Hz, 1H), 2.00-1.84 (m 3H), 1.75-1.60 (m, 3H), 1.60-1.50 (m, 1H).

Formation of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S)-3-methoxycyclohexyl)pyrimidin-4-amine(552).

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-(3-methoxycyclohexyl)pyrimidin-4-amine,27b, (0.08 g, 0.15 mmol) in THF were added a few drops of NaOMe. Thereaction mixture was stirred at room temperature for 20 min. To thereaction mixture was added ethyl acetate and brine. The organic phasewas separated, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was dissolved in CH₃CN/H₂O and the mixture was purified bypreparatory HPLC to afford 23 mg of the desired product, 552.

¹H NMR (300 MHz, CD₃OD) δ 8.70 (d, J=2.3 Hz, 1H), 8.45 (s, 1H), 8.35(d,J=2.3 Hz, 1H), 8.25(d, J=5.4 Hz, 1H), 4.35 (m, 1H), 3.52 (m, 1H), 3.4(s, 3H), 2.53 (d, J=12.1 Hz, 1H), 2.18 (d, J=11.4 Hz, 2H), 2.05-1.95 (m,1H), 1.65-1.4 (m, 3H), 1.38-1.25 (m, 1H); LCMS RT=2.22 min (M+1) 376.23

(3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol(524).

LCMS RT=2.0 (M+1) 362.48.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylethylcarbamate (608).

LCMS RT=2.9 (M+1) 433.4.

Formation of3-(2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanone(28a).

To a solution of3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanol,27a, (0.54 g. 1.05 mmol) in 20 ml CH₂Cl₂ was added Dess-Martinperiodinane (0.62 g, 1.47 mmol). The suspension was stirred at roomtemperature for 6 h. The reaction mixture was filtered through celiteand the filtrate was concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (45% ethyl acetate/hexanesgradient) to afford 430 mg of the desired product.

¹H NMR (300MHz, CDCl3) δ 8.66 (d, J=2.4 Hz, 1H), 8.42(s1H), 8.31 (d,J=2.3 Hz, 1H), 8.05-8.02 (m, 3H), 7.24-7.19 (m, 2H), 2.99 (d, J=5.2 Hz,1H), 4.56 (s, 1H), 2.85 (dd, J=4.7, 13.9 Hz, 1H), 2.50-2.40 (m, 3H),2.40 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 2H).

Formation of3-(2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(28b).

To a cold (0° C.) solution of3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone,28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide(3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirredat 0° C. for lh. The reaction mixture was diluted with ethyl acetate andaqueous saturated NH₄Cl solution. The organic phase was separated, dried(MgSO₄), filtered and concentrated in vacuo. The products were purifiedby silica chromatography with DCM and methanol, two products were eludedwith 95% DCM and 5% methanol no separation. The two diastereomers weretaken on as a mixture without further purification.

LCMS (10-90% 3/5 min(grad/run) w/FA) indicated 2 peaks for the desiredproducts. Peak 1: retention time=4.04 min (M+1: 530.42); peak 2:retention time=4.18min (M+1: 530.45).

Formation of(3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(571 and 572).

To a solution of3-(2-(5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol,28b, in THF was added a few drops of 25% sodium methoxide at roomtemperature. The reaction mixture was stirred at room temperature for 5min. The reaction mixture was diluted with ethyl acetate and brine. Theorganic phase was separated, dried (MgSO₄), filtered and concentrated invacuo. The product was purified by preparatory HPLC to afford twodiastereomers.

Diastereomer 1-571.

¹H NMR (300 MHz, CD₃OD) δ 8.78 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 8.36 (s,1H), 8.30 (dd, J=5.6, 9.9 Hz, 1H), 4.85 (m, 1H) 2.25-1.95 (m, 3H),1.86-1.6(m 4H), 1.40-1.3(m 2H), 1.3(s, 3H); LCMS RT 2.39 (M+1) 376.42.

Diastereomer 2-572.

¹H NMR (300 MHz, CD3OD) 6 8.66 (d, J=2.1 Hz, 1H), 8.55 (d, J=2.7 Hz,1H), 8.38 (s, 1H), 8.258 (dd, J=5.6, 9.5 Hz, 1H), 4.6(s, 1H), 2.00-1.50(m, 9H), 1.30 (s, 3H); LCMS RT 1.97 (M+1) 376.41.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethynylcyclohexanol(617 and 618).

Diastereomer 1—617: LCMS RT=3.6 (M+1) 386.4.

Diastereomer 2—618: LCMS RT=3.2 (M+1) 386.3.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-vinylcyclohexanol(627 and 628).

Diastereomer 1—627: LCMS RT=4.0 (M+1) 388.4.

Diastereomer 2—628: LCMS RT=3.7 (M+1) 388.4.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(hydroxymethyl)cyclohexanol(646).

LCMS RT=3.4 (M+1) 392.4.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethylcyclohexanol(626).

LCMS RT=4.1 (M+1) 390.4.

Formation of (3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol(29a).

The starting racemic alcohol, (3S)-3-aminocyclohexanol, was preparedfollowing the procedure described by Bernardelli, P., Bladon, M.,Lorthiois, E., Manage, A., Vergne, F. and Wrigglesworth, R., TetrahedronAsymmetry 2004, 15 , 1451-1455.

(3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol was preparedaccording to the procedure for compound 16a using(3S)-3-aminocyclohexanol, afforded desired product, 29a, as a solid.

Formation of (S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone(29b).

To 700 ml DCM solution of 7.9 g (32.16 mmol)(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 29a, (7.90g, 32.16 mmol) in CH₂Cl₂ (700 mL) was added Dess-Martin reagent (17.73g, 41.81 mmol). The reaction mixture was stirred at room temperature for20 hours until TLC chromatography indicated reaction was complete. Thereaction mixture was filtered through a pad of celite, and the resultingfiltrate was washed with 200 mL of aqueous saturated NaHCO₃ solution and200 mL brine. The organic phase was dried with MgSO₄, filtered and thesolvent was removed under reduced pressure. The product was purified bysilica gel chromatography (50% EtOAc/hexanes) to afford 7.3 g of thedesired product, 29b (93% yield).

¹H NMR (300MHz, CD3OD) δ H NMR (300 MHz, CDCl3) δ 7.96-7.93 (m, 1H),7.28 (s, 1H), 5.12 (s, 1H), 4.57-4.48 (m, 1H), 2.87 (dd, J=4.8, 14.0 Hz,1H), 2.51-2.23 (m, 4H), 2.12-2.02 (m, 1H); LCMS RT=2.97 (M+1) 244.26.

Formation of(3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol (29c,29d).

To a solution of(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (1.83 g,7.49 mmol) in THF (100 mL) was added methylmagnesium bromide (21.4 ml of1.4M solution, 29.96 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 5 minutes. To the reaction mixture wasadded aqueous saturated NH₄Cl solution and EtOAc. The organic phase waswashed with brine and dried with MgSO₄, filtered and concentrated invacuo. The two spots were separated by silica gel chromatography (120 gsilica gel column).

Fraction-1 (29c): ¹H NMR (300MHz, CD₃OD) δ δ 6 7.81 (d, J=2.8 Hz, 1H),7.28 (d, J=0.5 Hz, H), 4.47 (q, J=3.8 Hz, 1H), 1.92-1.87 (m, 2H),1.82-1.77 (m, 1H), 1.69 (dd, J=4.2, 14.0 Hz, 2H) and 1.56-1.48 (m, 4H)ppm; LCMS RT=3.43 (M+1) 260.3.

Fraction-2 (29d): ¹H NMR (300MHz, CD₃OD) δ 7.87 (d, J=2.8 Hz, H), 7.28(s, H), 4.95 (d, J=5.0 Hz, 1H), 4.45-4.33 (m, 1H), 2.17 (s, H),2.12-2.06 (m, 1H), 1.93-1.78 (m, 1H), 1.71 (dd, J=3.1, 5.6 Hz, 2H),1.39-1.25 (m, 4H) and 1.19-1.05 (m, 1H) ppm; LCMS RT=3.10 (M+1) 260.29.

Formation of(3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(29e, 290.

Degassed a solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(1.46 g, 3.37 mmol),(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-methyl-cyclohexanol,29c, (0.72 g, 2.81 mmol) and Na₂CO₃ (4.21 mL of 2M solution, 8.433 mmol)in dimethoxyethane (15 mL) for 30 min with nitrogen. To the reactionmixture was added palladium tetrakis-triphenylphosphane (0.16 g, 0.14mmol). The reaction mixture was heated at 130° C. in Q-tube apparatusfor 45 minutes. The reaction mixture was filtered through a pad of 1 cmof silica gel and 2 cm celite. The product was purified by silica gelchromatography (hexanes/EtOAc) to afford the desired product, 29e (63%yield).

¹H NMR (300MHz, CD₃OD) δ 8.81 (d, J=2.4 Hz, 1H), 8.50 (s, 1H), 8.38 (d,J=2.4 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 8.04 (d, J=3.3 Hz, 1H), 7.29 (d,J=8.1 Hz, 2H), 6.85 (d, J=5.7 Hz, H), 4.58 (t, J=3.7 Hz, 1H), 2.39 (s,H), 1.98-1.93 (m, 2H), 1.86 (d, J=4.0 Hz, 2H), 1.72-1.56 (m, 5H), 1.36(d, J=3.8 Hz, 3H) and 1.30-1.26 (m, 1H) ppm.

LCMS RT=4.62 (M+1) 530.4.

The diastereomer, 29f, was made according to the same procedure as 29e,substituting 29d as the starting material for the Suzuki couplingprocedure.

¹H NMR (300 MHz, CD₃OD) δ 8.89 (d, J=2.4 Hz, 1H), 8.55 (s, 1H), 8.39 (d,J=2.4 Hz, 1H), 8.09 (t, J=8.4 Hz, 2H), 8.08 (s, 1H), 7.29 (d, J=8.2 Hz,2H), 4.89 (d, J=6.6 Hz, 1H), 4.55 (m, 1H), 2.39 (s, 3H), 2.24 (t, J=1.8Hz, 2H), 2.02-1.93 (m, 1H), 1.77 (t, J=3.3 Hz, 2H), 1.46-1.33 (m, 5H)and 1.29-1.15 (m, 1H) ppm.

LCMS RT=4.36 (M+1) 530.3.

Formation of(3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(655, 656).

To a solution of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanol,29f, (2.85 g, 5.38 mmol) in THF (200 mL) was added 1.5 ml 25% W/W sodiummethoxide solution at room temperature. The reaction mixture wasimmediately injected into LC/MS. LC/MS indicated the reaction wascomplete. The reaction mixture was diluted with 200 ml EtOAc and theorganic phase was washed twice with aqueous saturated NaHCO₃ and thentwice with brine. The organic phase was dried with MgSO₄, filtered andconcentrated in vacuo. The product was purified by silica gelchromatography (80 g silica, 5% MeOH/CH₂Cl₂) to afford 1.7 g of thedesired product. The resulting product was dissolved in 70 ml THF, to itwas added 1.8 ml 5M HCl/IPA. The resulting suspension was stirred for 1hour at room temperature. The solvent was removed under reduced pressureto afford 1.7 g of the desired product, 655 as an HCl salt.

¹H NMR (300MHz, CD₃OD) δ 9.54 (s, 1H), 8.86 (d, J=2.3 Hz, 1H), 8.31 (d,J=2.4 Hz, 1H), 8.15 (d, J=2.7 Hz, 1H), 8.04 (d, J=3.5 Hz, 1H), 7.28 (s,H), 6.66 (s, 1H), 4.62-4.59 (m, 1H), 1.96-1.88 (m, 4H), 1.81 (dd, J=4.5,14.9 Hz, 1H) and 1.68-1.57 (m, 6H) ppm; LCMS RT=4.01 (M+1) 376.4.

The corresponding diastereomer, 656, can be prepared in the samefashion.

Formation of 1-methyl-7-oxabicyclo[4.1.0]heptane (30a)

To a cold (0° C.) solution of 1-methylcyclohexene (3.0 g, 31.2 mmol) inCH₂Cl₂ (150 mL) was added mCPBA (8.4 g, 48.7 mmol). The reaction mixturewas stirred at 0° C. for 1 h. The reaction mixture was diluted intoaqueous saturated NaHCO₃ solution and extracted with ether. The organicphase was washed again with aqueous saturated NaHCO₃ solution, dried(MgSO₄), filtered and concentrated in vacuo to afford the desiredproduct as anoil that was used without further purification.

Formation of 2-amino-1-methylcyclohexanol (30b)

To a solution of 1-methyl-7-oxabicyclo[4.1.0]heptane, 30a, (1.0 g, 7.1mmol) in water was added ammonium hydroxide (6.0 mL, 154.1 mmol). Themixture was heated to 50° C. for 48 hours. The mixture was diluted withwater, extracted with EtOAc and then twice with 20%MeOH/CHCl₃. Theorganic phases were dried (MgSO₄), filtered and concentrated in vacuo toprovide the desired product, 30b, as an amorphous white solid.

¹H NMR (300.0 MHz, DMSO) δ 2.44 (dd, J=3.4, 10.8 Hz, 1H), 1.64-1.45 (m,4H), 1.28-1.01 (m, 4H) and 0.97 (s, 3H) ppm.

Formation of2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(30c)

To a solution of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,1a, (0.97 g, 2.09 mmol) and 2-amino-1-methylcyclohexanol, 30b, (0.40 g,3.13 mmol) in DMF (10 mL) was added ^(i)Pr₂NEt (0.73 mL, 4.17 mmol). Thereaction mixture was heated at 90 C for 17 hours. The reaction mixturewas cooled to room temperature and diluted into aqueous saturated NaClsolution. The aqueous phase was extracted twice with EtOAc. The organicphases were washed with twice with aqueous saturated NaCl solution,dried (MgSO₄), filtered and concentrated in vacuo. The crude residue waspurified via silica gel chromatography (0-50% EtOAc/hexanes-loaded withCH₂Cl₂) to afford the desired product, 30c, as a white solid.

¹H NMR (300.0 MHz, DMSO) δ 9.00 (d, J=2.4 Hz, 1H), 8.49 (dd, J=2.4, 10.3Hz, 1H), 8.42 (s, 1H), 8.23 (d, J=4.1 Hz, 1H), 8.10-8.01 (m, 2H),7.52-7.43 (m, 2H), 7.21 (d, J=9.1 Hz, 1H), 4.52 (s, 1H), 4.28 (s, 1H),2.35 (s, 3H), 1.78-1.50 (m, 6H), 1.34 (m, 2H) and 1.15 (s, 3H).

LCMS RT=4.1 (M+1) 530.6.

Formation of2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanol(562 and 563)

To a solution of2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanol,30c, (0.41 g, 0.77 mmol) in THF was added 1M LiOH solution. The reactionmixture was heated in microwave at 120° C. for 5 minutes. The reactionmixture diluted with water, twice extracted with EtOAc and then twicewith 10% MeOH/CH₂Cl₂.The combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified viasilica gel chromatography (5-20% MeOH: CH₂Cl₂) to afford a white solidas a mixture of trans-enantiomers. The two trans-enantiomers wereseparated by chiral preparatory HPLC to afford 562 and 563.

Enantiomer 1—563: ¹H NMR (300.0 MHz, DMSO) δ 12.32 (s, 1H), 8.86 (d,J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.92(d, J=8.2 Hz, 1H), 4.56 (s, 1H), 4.31 (dd, J=5.9, 8.6 Hz, 1H), 1.89-1.35(m, 8H) and 1.17 (s, 3H); LCMS RT=2.5 (M+1) 376.4.

Formation of (1R, 2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (31b).

The starting racemic diol, 31a, (1R, 2S,3S)-3-aminocyclohexane-1,2-diol, was prepared following the proceduredescribed in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al.To a solution of racemic diol 31a (0.66 g, 5.00 mmol) in acetonitrile (5mL) and isopropanol (5 mL) was added 2,4-dichloro-5-fluoro-pyrimidine(0.84 g, 5.03 mmol) and ^(i)Pr₂NEt (3.25 g, 4.38 mL, 25.20 mmol). Thereaction mixture was sealed and heated to 100° C. for 90 minutes andthen concentrated to dryness. The crude was purified via silica gelchromatography (40%-100% EtOAc/Hex) to afford a racemate, which wasfurther purified via chiral HPLC separation to give compound 31b (0.26g) as a white solid.

¹H NMR (300 MHz, MeOH—d4) δ 7.80 (s, 1H), 4.60 (s, 6H), 4.10 (m, 1H),3.80 (s, 1H), 3.60 (m, 1H), 3.20 (s, 1H), 3.15 (s, 2H), 1.50-1.70 (m,5H), 1.20 (m, 1H) ppm.

LCMS RT=2.8 (M+1) 262.0, (M−1) 260.1.

Formation of (1R, 2S,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(31c).

To a deoxygenated solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.22 g, 0.51 mmol) and (1R, 2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b,(0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate(0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030mmol) . The reaction was sealed and heated to 120° C. for 15 minutes inthe microwave. The rxn was diluted with EtOAc and filtered thruflorisil. The solution was concentrated to crude and purified via silicagel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g)as a pink solid.

LCMS RT=3.8 (M+1) 532.2, (M−1) 530.2.

Formation of (1R, 2S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(632).

To a solution of (1R, 2S,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol,31c, (0.11 g, 0.21 mmol) in THF was added TBAF (0.23 g, 0.84 mmol). Thereaction was aged at room temperature 1 hour, quenched with 1N HCl (1ml), and purified via reverse phase chromatography (5-70% MeCN/H₂O with0.1% TFA). The product was desalted on an SPE bicarbonate cartridge,concentrated to dryness, and then triturated from MeOH to provide 18 mgof compound 632.

¹H NMR (300 MHz, MeOH—d4) δ 6 8.42 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H),7.70 (s, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 1.75 (m, 5H),1.50 (m, 1H) ppm.

LCMS RT=3.0 (M+1) 378.2, (M−1) 376.0.

Formation of (1S, 2S, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (32b).

The starting racemic diol, 32a, (1S, 2S,3S)-3-aminocyclohexane-1,2-diol, was prepared following the proceduredescribed in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al.According to the method for compound 632, except use the racemate ofdiol 32a (0.07 g, 0.53 mmol), to give compound 32b (0.03 g, 0.11 mmol)as a white solid.

¹H NMR (300 MHz, MeOH—d4) δ 7.90 (s, 1H), 4.45 (m, 1H), 3.80 (s, 1H),3.62 (s, 1H), 1.40-1.80 (m, 6H), 0.85 (m, 1H) ppm.

LCMS RT=2.7 (M+1) 262.0.

Formation of (1S, 2S, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(32c).

According to the method for compound 31c, except use compound 32b (0.03g, 0.11 mmol), to give compound 32c (0.06 g, 0.11 mmol).

LCMS RT=3.9 (M+1) 532.2, (M−1) 530.3.

Formation of (1S, 2S, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(615).

According to the method for compound 624, except use compound 32c (0.06g, 0.11 mmol) to give compound 615 (0.015 g, 0.035 mmol) as a whitesolid.

¹H NMR (300 MHz, MeOH-d4) δ 8.83 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H),8.30 (s, 1H), 4.00 (bs, 2H), 0.60-0.90 (m, 4H), 0.50 (m, 2H) ppm.

LCMS RT=3.7 (M+1) 378.3, (M−1) 376.3.

Formation of (1R, 2R, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol (33b).

The starting racemic diol, 33a, (1R, 2R,3S)-3-aminocyclohexane-1,2-diol, was prepared following the proceduredescribed in: Org. Lett. (2009) 6, 1333, Davies, et. al. According tothe method for compound 632, except use the racemate of diol 33a (0.13g, 1.01 mmol) to give compound 33b (0.14 g, 0.53 mmol) as a white solid.

¹H NMR (300 MHz, MeOH-d4) δ 7.90 (s, 1H), 4.05 (m, 2H), 3.70-3.80 (m,0.6H), 1.95 (bs, 2.5H), 1.70 (m, 1.6H), 1.30-1.60 (m, 5.4H) ppm; ¹³C-APT NMR (300 MHz, MeOH-d4) δ 148.6, 145.2, 140.0, 139.8, 78.9, 75.2,55.4, 49.15 (m, MeOH—d4), 33.9, 31.9, 22.4 ppm.

LCMS RT=2.4 (M+1) 262.0, (M−1) 260.1.

Formation of (1R, 2R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(33c).

According to the method for compound 31c, except use compound 33b (0.07g, 0.26 mmol) to give compound 33c (0.008 g, 0.015 mmol). DME was usedas solvent, not acetonitrile. LCMS RT=4.2 (M+1) 532.3, (M−1) 530.3.

Formation of (1R, 2R, 3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol(625).

According to the method for compound 624, except use compound 33c (0.008g, 0.015 mmol to give compound 625 (0.005 g, 0.012 mmol).

¹H NMR (300 MHz, MeOH-d4) δ 8.80 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H),8.20 (s, 1H), 4.5 (m, 1H), 3.55 (m, 2H), 2.12 (m, 2H), 1.95(m, 1H), 1.61(m, 2H), 1.58 (m, 1H) ppm.

LCMS RT=2.4 (M+1) 378.2, (M−1) 376.2.

The following compounds, 631, 616 and 624, are enantiomers of 632, 615and 625 and can be prepared by isolation from chiral preparatory HPLCchromatography from their respective enantiomeric mixtures.

Formation of (1S,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (553).

A mixture of5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,1a, (0.49 g, 1.05 mmol), (1S,2S)-2-amino-cyclohexanecarboxylic acid(0.30 g, 2.10 mmol), freshly ground Na₂CO₃ (0.22 g, 2.10 mmol), and^(i)Pr₂NEt (0.37 mL, 2.10 mmol) in THF (10 mL) and CH₃CN (2 mL) wereheated in a sealed vessel to 130° C. for 30 minutes under microwaveirradiation. The mixture was cooled to room temperature. A solution of1N LiOH (3.1 mL, 3.1 mmol) was added and the mixture was stirred at 120°C. for 10 minutes under microwave irradiation. The mixture was acidifiedwith 1N HCl until pH 2 under vigorous stirring. The newly formed solidwas collected by vacuum filtration. The solid was washed with smallamounts of water and EtOAc. The solid was dried in vacuo to provide thedesired product.

¹H NMR (300 MHz, MeOD) δ 8.89 (d, J=2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d,J=2.3 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 4.75 (m, 1H), 2.75-2.66 (m, 1H),2.25-2.16 (m, 2H), 1.99-1.89 (m, 2H), 1.71-1.29 (m, 4H) ppm; LCMS RT=2.0min, (M+H) 390.4.

Other analogs that can be prepared in the same manner as 553 aredescribed below:

trans-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (541)

LCMS RT=2.4 min, (M+H) 390.5.

(1R,2R)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (554)

¹H NMR (300 MHz, MeOD) δ 8.89 (d, J=2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d,J=2.4 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 4.77 (m, 1H), 2.75-2.66 (m, 1H),2.24-2.17 (m, 2H), 1.94-1.89 (m, 2H) and 1.74-1.36 (m, 4H) ppm.

LCMS RT=2.3 min, (M+H) 390.4.

Cis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (559)

¹H NMR (300 MHz, MeOD) δ 8.75 (d, J=2.4 Hz, 1H), 8.38-8.35 (m, 2H), 8.24(d, J=5.1 Hz, 1H), 4.70-4.62 (m, 1H), 3.25-3.17 (m, 1H), 2.32 (m, 1H),2.14-1.80 (m, 4H) and 1.68-1.54 (m, 3H) ppm.

LCMS RT=2.3 min, (M+H) 389.8.

(1S,2R)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (579)

¹H NMR (300 MHz, d6-DMSO) δ 12.52 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.33(d, J=2.5 Hz, 2H), 8.30 (d, J=4.4 Hz, 1H), 7.57 (s, 1H), 4.53 (m, 1H),3.05 (m, 1H), 2.15-2.07 (m, 1H), 1.96 (m, 1H), 1.81-1.76 (m, 3H) and1.51 (m, 3H) ppm.

LCMS RT=2.9 min, (M+H) 390.4.

(1R,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (578)

1H NMR (300 MHz, d6-DMSO) δ 12.51 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.33(d, J=2.3 Hz, 2H), 8.29 (d, J=4.3 Hz, 1H), 7.55 (s, 1H), 4.53 (s, 1H),3.05 (m, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.79 (m, 3H) and 1.51 (m, 3H)ppm.

LCMS RT=2.8 min, (M+H) 390.4.

Cis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclopentanecarboxylicacid (558)

¹H NMR (300 MHz, MeOD) δ 8.78 (d, J=2.4 Hz, 1H), 8.38 (s, 1H), 8.33 (d,J=2.2 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 4.98 (dd, J=7.2 Hz, 1H),2.27-2.03 (m, 5H) and 1.86-1.76 (m, 1H) ppm.

LCMS RT=2.5 min, (M+H) 376.2.

(1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclopentanecarboxylicacid (566)

¹H NMR (300 MHz, d6-DMSO) δ 12.42 (s, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.29(m, 2H), 8.22 (d, J=4.1 Hz, 1H), 7.87 (s, 1H), 4.56-4.49 (m, 1H), 2.87(dd, J=8.4, 25.0 Hz, 1H), 2.87 (s, 1H), 2.42-2.33 (m, 1H), 2.15-2.04 (m,1H), 2.00-1.85 (m, 3H) and 1.81-1.70 (m, 1H) ppm.

LCMS RT=2.3 min, (M+H) 376.4.

(1S,3R)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclopentanecarboxylicacid (565)

¹H NMR (300 MHz, d6-DMSO) δ 12.48 (s, 1H), 8.71 (d, J=2.3 Hz, 1H),8.35-8.31 (m, 2H), 8.26 (d, J=4.3 Hz, 2H), 8.02 (s, 1H), 4.57-4.44 (m,1H), 2.87 (qn, J=8.3 Hz, 1H), 2.39-2.32 (m, 1H), 2.15-2.05 (m, 1H),2.00-1.86 (m, 3H) and 1.82-1.70 (m, 1H) ppm.

LCMS RT=2.4 min, (M+H) 376.4.

(1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (630)

Compound 630 was prepared in same fashion from intermediate 18c, byremoval of Cbz-protecting group and reaction with intermediate 1a,followed by removal of tosyl protecting group.

LCMS RT=3.2 min, (M+H) 390.4, (M-H) 388.1.

Trans-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylicacid (582)

¹H NMR (300.0 MHz, d6-DMSO) δ 12.46 (s, 1H), 8.72 (d, J=2.4 Hz, 1H),8.32-8.28 (m, 3H), 7.10 (d, J=7.1 Hz, 1H), 4.27-4.20 (m, 1H), 2.26 (d,J=10.1 Hz, 1H), 1.93 (m, 1H), 1.83 (m, 1H), 1.68-1.59 (m, 3H), 1.36 (m,2H) and 1.24 (s, 3H) ppm.

LCMS RT=3.2 min, (M+H) 404.4.

Racemictrans-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethylcyclohexanecarboxylicacid (586)

¹H NMR (300 MHz, MeOD) δ 8.93 (s, 1H), 8.85 (m, 2H), 8.93-8.87 (m, 1H),8.31 (dd, J=4.5, 1.2 Hz, 2H), 8.31 (dd, J=4.5, 1.2 Hz, 2H), 8.30 (d,J=2.3 Hz, 1H), 8.19 (d, J=5.0 Hz, 1H), 5.26-5.20 (m, 1H), 3.37 (dd,J=3.3 Hz, 1.6, 2H), 3.33 (ddt, J=6.6, 3.3, 1.6 Hz, 118H), 2.11 (dd,J=8.0, 5.8 Hz, 2H), 1.80 (tdd, J=21.2, 18.9, 11.6 Hz, 8H), 1.63-1.54 (m,3H), 0.86 (q, J=7.4 Hz, 4H) ppm.

LCMS RT=2.9 min, (M+H) 418.4.

Racemiccis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethylcyclohexanecarboxylicacid (585)

¹H NMR (300 MHz, MeOD) δ 8.80-8.76 (m, 1H), 8.37 (s, 1H), 8.35 (d, J=2.3Hz, 1H), 8.27-8.23 (m, 1H), 4.49-4.42 (m, 1H), 2.43-2.34 (m, 1H), 2.09(d, J=6.2 Hz, 1H), 1.98-1.36 (m, 12H), 0.94 (dd, J=11.3, 3.8 Hz, 3H)ppm.

LCMS RT=3.2 min, (M+H) 418.4.

(3S, 4R, 5R)-ethyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4-ethanamido-5-(pentan-3-yloxy)cyclohex-1-enecarboxylate(670)

¹H NMR (300.0 MHz, MeOD) δ 8.64 (d, J=2.3 Hz, 1H), 8.40 (s, 1H), 8.32(d, J=2.3 Hz, 1H), 8.29 (d, J=5.0 Hz, 1H), 6.96 (m, 1H), 4.84-4.80 (m,1H), 4.34 (m, 1H), 4.29-4.19 (m, 3H), 3.54-3.47 (m, 1H), 3.15-3.07 (m,1H), 2.68-2.58 (m, 1H), 1.92 (s, 3H), 1.59-1.51 (m, 4H), 1.26 (t, J=7.1Hz, 3H), 0.95 (t, J=7.4 Hz, 3H) and 0.89 (t, J=7.4 Hz, 3H) ppm

LCMS RT=3.6 (M+1) 559.4.

(3S, 4R,5R)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4-ethanamido-5-(pentan-3-yloxy)cyclohex-1-enecarboxylicacid (671)

¹H NMR (300.0 MHz, MeOD) δ 8.66 (d, J=2.3 Hz, 1H), 8.39 (s, 1H), 8.32(d, J =2.3 Hz, 1H), 8.29 (d, J=5.0 Hz, 1H), 6.97 (m, 1H), 4.82-4.79 (m,1H), 4.34 (m, 1H), 4.25 (dd, J=7.6, 10.1 Hz, 1H), 3.54-3.47 (m, 2H),3.11-3.04 (m, 1H), 2.65-2.57 (m, 1H), 1.91 (s, 3H), 1.59 (m, 4H), 0.95(t, J=7.4 Hz, 3H) and 0.89 (t, J=7.4 Hz, 3H) ppm

LCMS RT=3.1 (M+1) 531.4.

(1S, 2S)-ethyl2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(561)

To a mixed slurry of (1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-1-carboxylicacid, 553, (0.090 g, 0.231 mmol), in ethanol (1.5 mL) at roomtemperature was added HCl (0.577 mL of 4 M solution, 2.309 mmol). Thesolution was warmed to 50° C. After 6 hours, the mixture was basifiedwith 1N NaOH, brine was added and the aqueous layer was and extractedrepeatedly with EtOAc. The organic layer was dried over MgSO₄, andfiltered through a short plug of silica gel and concentrated in vacuo toprovide the desired product.

¹H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.19 (m, 2H), 7.99 (s, 1H), 4.61(m, 1H), 3.93 (m, 2H), 2.61 (m, 1H), 2.17-2.05 (m, 2H), 1.89-1.32 (m,7H) and 1.00 (m, 3H) ppm.

LCMS RT=2.7 min, (M+H) 418.4.

The following compounds can also be prepared in a manner similar to theone described in Scheme 36.

(1R, 2R)-ethyl2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(560)

¹H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.23-8.14 (m, 2H), 8.00 (m, 1H),4.61 (m, 1H), 3.96-3.92 (m, 2H), 2.61 (m, 1H), 2.14-2.04 (m, 2H),1.89-1.35 (m, 7H) and 1.04-0.99 (m, 3H) ppm.

LCMS RT=3.2 min, (M+H) 418.5.

(1S, 2S)-methyl2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(575)

¹H NMR (300 MHz, d6-DMSO) δ 8.76 (d, J=2.5 Hz, 1H), 8.26 (d, J=2.4 Hz,1H), 8.19 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H),4.47-4.37 (m, 1H), 3.40 (s, 3H), 2.68-2.59 (m, 1H), 2.05-1.97 (m, 2H),1.84-1.75 (m, 2H), 1.63-1.40 (m, 3H) and 1.31-1.23 (m, 1H) ppm.

LCMS RT=3.1 min, (M+H) 404.4.

(1S, 2S)-2-methoxyethyl2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(574)

¹H NMR (300 MHz, d6-DMSO) δ 8.74 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.4 Hz,1H), 8.19 (s, 1H), 8.12 (d, J=4.0 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 4.42(m, 1H), 4.02-3.86 (m, 2H), 3.35-3.23 (m, 2H), 3.08 (s, 3H), 2.69-2.60(m, 1H), 1.99 (m, 2H), 1.77 (m, 2H), 1.62-1.40 (m, 3H) and 1.27 (m, 1H)ppm.

LCMS RT=3.0 min, (M+H) 448.4.

(1R, 2R)-isopropyl 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(568)

¹H NMR (300 MHz, d6-DMSO) δ 8.80 (d, J=2.5 Hz, 1H), 8.27 (d, J=2.4 Hz,1H), 8.19 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 4.72(qn, J=6.2 Hz, 1H), 4.55-4.48 (m, 1H), 2.61-2.54 (m, 1H), 1.96 (m, 2H),1.77 (m, 2H), 1.63-1.41 (m, 3H), 1.30-1.23 (m, 1H) and 0.93 (d, J=6.2Hz, 6H) ppm.

LCMS RT=3.08 min, (M+H) 432.46.

(1S, 2S)-isopropyl2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate(569)

¹H NMR (300 MHz, d6-DMSO) δ 12.57 (s, 1H), 8.80 (d, J=2.4 Hz, 1H),8.36-8.28 (m, 4H), 4.75 (td, J=12.5, 6.2 Hz, 1H), 4.52 (m, 1H),2.65-2.56 (m, 1H), 2.00 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.42 (m, 3H),1.32-1.24 (m, 1H) and 0.94 (d, J=6.2 Hz, 6H) ppm.

LCMS RT=2.7 min, (M+H) 432.5.

Formation of ethyl 1-methyl-2-oxocyclohexanecarboxylate (37a):

The title compound was prepared following the procedure described in:Tetrahedron Letters (2005) 46, 681-685 and JCS, Perkin Trans 1(2000)3277-3289. Sodium hydride (1.48 g, 37.14 mmol, 60% in oil) was rinsedtwice with hexanes to remove oil and suspended in DMF (57 mL) at 0° C.Then, ethyl 2-oxocyclohexanecarboxylate (5.40 mL, 33.76 mmol) was addedover 5 minutes. The mixture was stirred for 20 minutes and Mel (2.21 mL,35.45 mmol) was added over 10 minutes. The mixture was warmed to roomtemperature and after 30 minutes, diluted with EtOAc (150 mL) andquenched with saturated NH₄Cl. The layers were separated and the aqueouslayer was extracted twice more with EtOAc (2×100 mL). The organic layerwas washed with brine (2×) dried over MgSO₄, filtered through silica geland concentrated to provide the desired product (37a).

Formation of 3a-methyl-4, 5, 6, 7-tetrahydrobenzo[c]isoxazol-3(3aH)-one(37b):

To a mixture of ethyl 1-methyl-2-oxo-cyclohexanecarboxylate, 37a, (2.05g, 11.10 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride(0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol). The mixture washeated to 65° C. overnight. The solution was concentrated in vacuo andthe crude material was partitioned between water and EtOAc. The aqueouslayer was extracted with EtOAc twice more. The combined organic phaseswere washed with brine, dried over MgSO₄, filtered and concentrated invacuo. The resulting residue was purified via silica gel chromatography(0-35% EtOAc/hexanes) to afford the desired product, 37b.

¹H NMR (300 MHz, CDCl₃) δ 2.72-2.65 (m, 1H), 2.29 (td, J=13.3, 6.3 Hz,1H), 2.18-2.09 (m, 1H), 2.07-2.03 (m, 1H), 1.84-1.79 (m, 1H), 1.76-1.56(m, 2H), 1.54-1.42 (m, 1H) and 1.40 (s, 3H) ppm.

Formation of trans-2-amino-1-methylcyclohexanecarboxylic acid (37c): Toa solution of 3a-methyl-4,5,6,7-tetrahydro-2,1-benzoxazol-3-one, 37b,(0.075 g, 0.490 mmol) in THF-H₂O (2.5 mL of 4:1 mixture) at roomtemperature was added fresh Al(Hg) amalgam. Aluminum was amalgamated bydipping small strips of Aluminum foil in 2% HgCl₂ solution, rinsing withwater and EtOH. After 1 hour, an additional 65 mg Al(Hg) was added andthe mixture was allowed to stir overnight. The thick gray emulsion thatformed was filtered through celite and rinsed with water and THF. Theclear solution was concentrated in vacuo, stripped with methanol and THFto remove residual water and concentrated in vacuo to provide thedesired product as a glassy solid as mixture of trans and cis isomers(-9:1) with the trans isomer as the predominant isomer. The product wassufficiently pure for use in the next reaction.

¹H NMR (300 MHz, MeOD) δ 2.91 (dd, J=3.9, 11.9 Hz, 1H), 2.25 (dd, J=1.9,13.4 Hz, 1H), 1.89-1.85 (m, 1H), 1.78-1.53 (m, 3H), 1.47-1.32 (m, 2H),1.21 (s, 3H) and 1.09-0.99 (m, 1H) ppm.

FIA (M+H) 158.1, (M-H) 156.2.

Formation of 2-amino-1-ethylcyclohexanecarboxylic acid:

This compound was prepared by the methods described above as aninseparable mixture of cis and trans isomers (70:30) and was usedwithout further purification.

An alternative scheme for the preparationcis-2-amino-1-alkyl-cyclohexanecarboxylic acid is exemplified above. Themethod is described in: (a) Nemoto, T.; Fukuyama, T.; Yamamoto, E.;Tamura, S.; Fukuda, T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org.Lett. 2007, 9 (5), 927-930. (b) Seebach, D,; Estermann, H. TetrahedronLett. 1987, 28 (27), 3103-3106.

(1R, 2S)-methyl2-(benzyloxycarbonylamino)-1-ethylcyclohexanecarboxylate(38b)

To a cold (−78° C.) solution of N-isopropylpropan-2-amine (0.77 mL, 5.49mmol) in THF (7 mL) was added, dropwise, n-butyllithium (3.43 mL of 1.6M solution, 5.49 mmol). The mixture was stirred at −78° C. for 10minutes. Then a solution of methyl (1S,2S)-2-benzyloxycarbonylaminocyclohexanecarboxylate, 38a, (0.40 g, 1.37mmol) in THF (2.5 mL) was added over a period of 3 minutes. After 15minutes, the mixture was warmed slightly (−40° C.) for 15 minutes andrecooled to −78° C. for a further 10 minutes. Then, iodoethane (0.86 g,0.44 mL, 5.49 mmol) was added, dropwise over 3-5 minutes. The reactionmixture was maintained at −78° C. for 2 hours and allowed to warm toroom temperature overnight. The reaction was quenched with 5 mL aqueoussaturated NH₄Cl solution, extracted with EtOAc (3×), washed successivelywith 1N HCl and brine. The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. Flash chromatography (SiO₂,0-20% EA/Hex slow gradient elution) provided 275 mg (63% yield) of thedesired product (38b). NMR indicated a diastereomeric ratio greater than10 to 1 (cis vs trans).

¹H NMR (300.0 MHz, MeOD) δ 7.35-7.28 (m, 5H), 6.62 (d, J=9.2 Hz, 1H),5.07 (dd, J=12.5, 16.6 Hz, 2H), 3.67 (s, 3H), 3.59 (td, J=10.0, 4.6 Hz,1H), 2.14 (m, 1H), 1.76-1.29 (m, 9H) and 0.83 (t, J=7.6 Hz, 3H) ppm.

(1R, 2S)-methyl 2-amino-1-ethylcyclohexanecarboxylate (38c)

A solution of methyl (1R,2S)-2-benzyloxycarbonylamino-1-ethyl-cyclohexanecarboxylate, 38b, (0.27g, 0.85 mmol) in MeOH (7.5 mL) was purged with nitrogen and a catalyticamount of Pd (5% Pd on carbon) was added. The solution was placed underH₂ atmosphere and stirred at room temperature. After 1 hour, the MeOHsolution suspension was filtered through celite, and concentrated invacuo to provide the desired product (138 mg, 88% yield). The materialwas diluted in acetonitrile and concentrated to remove residualmethanol.

¹H NMR (300.0 MHz, MeOD) δ 3.69 (s, 3H), 2.71 (m, 1H), 2.07-2.01 (m,1H), 1.82 (m, 2H), 1.71-1.27 (m, H), 1.64 (m, 2H), 1.56-1.27 (m, 5H) and0.85 (t, J=7.5 Hz, 3H) ppm.

A general method for the synthesis oftrans-2-amino-1-alkyl-cyclohexanecarboxylic acids is shown in the schemeabove.

Benzyl 2-oxocyclohexanecarboxylate (39b)

This compound was prepared following literature procedures described in:Matsuo, J. etal. Tetrahedon: Asymmetry 2007, 18, 1906-1910.

Benzyl 1-methyl-2-oxocyclohexanecarboxylate (39c)

This compound was prepared following the literature procedures describedin: (a) Hayashi, Y.; Shoji, M.; Kishida, S. Tetrahedron Lett. 2005, 46,681-685. (Winfield, C. J.; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T. D.H. J. Chem. Soc., Perkin Trans. 1, 2000, 3277.

Trans-Benzyl 2-(benzylamino)—1-methylcyclohexanecarboxylate(39d)-(racemic trans)

To a solution of benzyl 1-methyl-2-oxo-cyclohexanecarboxylate, 39c,(0.50 g, 2.03 mmol) and benzylamine (0.61 g, 0.63 mL, 5.75 mmol) indichloromethane (10.0 mL), was added TiCl₄ (1.93 mL of 1 M solution,1.93 mmol) dropwise, at room temperature. The mixture was stirred for 2hours. The mixture was cooled to 0° C. and a solution of NaBH₃CN (0.21g, 3.34 mmol) in MeOH was added dropwise over a period of 3 minutes.After 15 min, the solution was warmed to RT and stirred for anadditional 45 min. Then, the mixture was diluted with EtOAc, quenchedwith 10 mL 1M NaOH. The mixture was partitioned with Et₂O and theaqueous layer was extracted several times with Et₂O (2×) and EtOAc (1×).The combined organic phases were dried over MgSO₄, filtered andconcentrated in vacuo. Flash chromatography (SiO₂, 0-50% EtOAc-Hexanesgradient elution) and isolation of the major component provided thedesired product (320 mg) as a single racemic trans isomer.

¹H NMR (300.0 MHz, MeOD) δ 7.34-7.16 (m, 10H), 5.07 (dd, J=12.4, 31.2Hz, 2H), 3.78 (d, J=13.0 Hz, 1H), 3.57 (d, J=13.0 Hz, 1H), 2.96 (m, 1H),1.86 (m, 1H), 1.74-1.57 (m, 3H), 1.52-1.25 (m, 4H) and 1.20 (s, 3H) ppm.

Trans-2-Amino-1-methylcyclohexanecarboxylic acid (39e)

To a solution of racemic trans-benzyl (1s,2S)-2-(benzylamino)-1-ethyl-cyclohexanecarboxylate, 39d, (0.32 g, 0.91mmol) in MeOH (12.8 mL), was added Pd (5% Pd on carbon, 0.07 g). Thesolution was degassed and placed under 50 PSI H₂ (Parr shaker)overnight. The mixture was filtered through celite and the filtrate wasrinsed with MeOH. Concentration of the mother liquor followed byacetonitrile azeotrope (2×) to remove residual MeOH provided the desiredproduct (162 mg).

¹H NMR (300.0 MHz, MeOD) δ 3.22 (m, 1H), 1.93 (m, 1H), 1.77 (m, 2H),1.57-1.23 (m, 5H) and 1.17 (s, 3H) ppm.

trans-2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylicacid (39f)

To a vessel charged with5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,15a, (0.27 g, 0.58 mmol) andtrans-2-amino-1-methyl-cyclohexanecarboxylic acid, 39e, (0.08 g, 0.47mmol) and freshly ground Na₂CO₃ (0.19 g, 1.75 mmol) was added anhydrousTHF (4.5 mL) and CH₃CN (0.9 mL). The vessel was sealed and heated to135° C. for 35 min (microwave irradiation). LC-MS indicated completeconsumption of starting material. Next, the reaction mixture was slowlypoured into a vigorously stirred solution of 1N HCl (13.5 mL). The pH ofthe final solution was 1-2. The mixture was extracted with EtOAc (3×),dried over Na₂SO₄ and filtered through Celite and concentrated in vacuo.Flash chromatography (SiO₂, 0-10% MeOH-dichloromethane, gradientelution) provided a sticky yellow foam, which was suspended inacetonitrile. Sonication followed by evaporation of the solvent providedwhite amorphous solid (240 mg, 74% yield) as a racemic mixture of transstereoisomers.

¹H NMR (300.0 MHz, MeOD) δ 9.02 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.33(d, J=2.4 Hz, 1H), 8.09-8.05 (m, 3H), 7.38 (d, J=8.1 Hz, 2H), 5.04 (dd,J=3.6, 9.5 Hz, 1H), 2.38 (s, 3H), 2.09 (m, 1H), 1.83-1.59 (m, 7H), 1.29(s, 3H) and 1.23 (m, 1H) ppm.

LCMS RT=4.00 min, (M+H) 558.34.

Trans-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylicacid (643)

To a slurry of racemictrans-2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]Thyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylicacid, 39f, (0.047 g, 0.084 mmol) in CH₃CN (2.35 mL) was added HCl (1.26mL of 4 M solution, 5.05 mmol) in dioxane. The suspension became a clearsolution. The vial was sealed and heated to 80° C. for 2 hours duringwhich time a thick slurry formed. The slurry was allowed to cool to roomtemperature overnight. Additional CH₃CN was added and the mixture wascentrifuged. The organic layer was discarded and the solid wastriturated with CH₃CN three times more to provide an amorphous whitesolid as racemic mixture of trans stereoisomers.

¹H NMR (300.0 MHz, MeOD) δ 8.98 (d, J=2.3 Hz, 1H), 8.45 (s, 1H), 8.38(d, J=2.3 Hz, 1H), 8.30 (d, J=5.7 Hz, 1H), 5.26-5.22 (m, 1H), 2.17-2.10(m, 1H), 1.87-1.82 (m, 4H), 1.68-1.59 (m, 3H) and 1.36 (s, 3H) ppm.

LCMS RT=3.30 min, (M+H) 404.36.

Formation of 4-tert-butyl-2-chloro-5-fluoro-6-(methylthio)pyrimidine(40a)

To a cold (0° C.) solution of tert-butylmagnesium chloride (7.5 mL, 1Msolution in THF, 7.5 mmol) in THF (15 mL) was added slowly a solution of2-chloro-5-fluoro-4-(methylthio)pyrimidine (0.9 g, 5.0 mmol) in1,2-dimethoxyethane (5 mL). The reaction mixture was stirred at 15° C.for 1 hour, then cooled to 0° C. and triethylamine (0.7 mL, 5.0 mmol)was added, followed by the addition of a solution of iodine (1.3 g, 5.0mmol) in tetrahydrofuran (3 mL). Water (10 mL) was added to quench thereaction and pH was adjusted to 1 using 6N hydrochloric acid. Theaqueous phase was extracted twice with ethyl acetate (2×15 mL). Thecombined organic phases were washed with aqueous sodium thiosulfate andthen brine, dried over MgSO₄, filtered and concentrated in vacuo to givea brown solid which was used without further purification.

¹H NMR (300.0 MHz, CDCl₃) δ 2.52 (s, 3H), 1.30 (s, 9H) ppm.

LCMS (M+1) 233.0.

Formation of3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-1]pyridine(40b)

To a degassed solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.22 g, 0.50 mmol),4-tert-butyl-2-chloro-5-fluoro-6-thiomethoxypyrimidine, 40a, (0.12 g,0.50 mmol) in 1,2-dimethoxyethane (3 mL) and aqueous Na₂CO₃ (0.75 mL of2 M solution, 1.5 mmol) was addedtetrakis(triphenylphosphine)palladium(O) (0.03 g, 0.03 mmol). Thereaction mixture was degassed for an additional 15 minutes. The mixturewas heated in a microwave at 150° C. for 20 minutes. Ethyl acetate (15mL) was added. The organic layer was separated and washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The resultingcrude residue was purified by silica gel chromatography (0%-100%EtOAc/hexanes) to afford the desired product, 40b (47 mg).

¹H NMR (300 MHz, CDCl₃) δ 10.82 (br, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.27(d, J=2.3 Hz, 1H), 8.20 (dd, J=7.2, 2.2 Hz, 1H), 7.18 (s, 1H), 2.63 (s,3H), 1.41 (s, 9H) ppm.

LCMS (M+1) 352.3.

Formation of3-(tert-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (40c)

To the solution of3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine,40b, (0.05 g, 0.11 mmol) in CH₂Cl₂ (3.4 mL) was added mCPBA (0.02 g,0.11 mmol). The reaction mixture was stirred for 1 h. The reactionmixture was diluted with CH₂Cl₂ (10 mL) and saturated NaHCO₃ solution (5mL). The aqueous layer was extracted with CH₂Cl₂ (10 mL). The combinedorganic phases were washed again with aqueous saturated NaHCO₃ solution,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thedesired product that was used without further purification.

¹H NMR (300 MHz, CDCl₃) δ 10.93 (br, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.34(s, 1H), 8.25 (d, J=2.2 Hz, 1H), 7.19 (s, 1H), 2.98 (s, 3H), 1.47 (s,9H) ppm.

LCMS (M+1) 368.3.

Formation of (/S,2S)-2-(6-tert-butyl-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylicacid (629).

A mixture of3-(tert-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine,40c, (0.05 g, 0.14 mmol), (1S, 2S)-2-amino-cyclohexanecarboxylic acid(0.04 g, 0.27 mmol), freshly ground Na₂CO₃ (0.04 g, 0.41 mmol), and^(i)Pr₂NEt (0.37 mL, 0.27 mmol) in THF (1 mL) and CH₃CN (0.5 mL) washeated in a sealed vessel to 140° C. for 30 minutes under microwaveirradiation. The mixture was cooled to room temperature. A solution of1N HCl (0.5 mL, 0.5 mmol) was added and the mixture was concentrated togive a yellow solid, which was purified by reverse phase HPLC (0%-50%methanol in water) to afford the desired product, 629, as off-whitesolid.

¹H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.28 (d,J=2.4 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 4.34 (m,1H), 2.62 (m, 1H), 2.05 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H), 1.39 (s,9H) and 1.26-1.17 (m, 2H) ppm.

LCMS (M+1) 446.23.

Formation of3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylpyrrolidin-2-one(379)

A solution of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reactionwas heated at 140° C. for 20 minutes. The reaction mixture was cooled toroom temperature and then treated with 0.5 mL of 25% NaOMe in MeOH andheated at 50° C. for 15 min. The mixture was then partitioned betweenaqueous saturated Na₂CO₃ solution and EtOAc. The aqueous layer wasextracted with EtOAc twice more and the combined organic phases wereconcentrated in vacuo. The crude material was purified by preparativeHPLC. The isolated product was filtered through basic resin to removeresidual TFA and provide the desired product.

¹H NMR (300 MHz, MeOD) δ 8.72 (d, J=2.3 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H),8.11-8.07 (m, 2H), 4.94 (t, J=9.3 Hz, 1H), 3.64-3.51 (m, 2H), 2.97 (s,3H), 2.68-2.54 (m, 1H) and 2.37-2.23 (m, 1H) ppm.

LCMS RT=2.3 min, (M+H) 361.3.

The following compounds can also be prepared in a manner similar to theone described in Scheme 41.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-2-one(380)

¹H NMR (300 MHz, MeOD) δ 8.79 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H),8.13 (s, 1H), 8.07 (d, J=3.9 Hz, 1H), 4.91 (dd, J=8.7, 10.6 Hz, 1H),3.61-3.46 (m, 2H), 2.68-2.58 (m, 2H) and 2.48-2.31 (m, 1H) ppm.

LCMS RT=2.3 min, (M+H) 347.3.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylpiperidin-2-one(397)

¹H NMR (300.0 MHz, DMSO) δ 8.65 (d, J=2.5 Hz, 1H), 8.27 (d, J=2.4 Hz,1H), 8.20-8.19 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 4.78-4.74 (m, 1H), 3.41(t, J=5.4 Hz, 2H), 3.17 (MeOH), 2.89 (s, 3H), 2.50 (DMSO), 2.18-2.15 (m,1H) and 1.99 (d, J=7.4 Hz, 2H) ppm.

LCMS RT=2.2 min, (M+H) 375.4.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-2-one(416)

LCMS RT=1.6 min, (M+H) 361.3.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azepan-2-one(417)

¹H NMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.28 (d,J=2.4 Hz, 1H), 8.21 (t, J=3.7 Hz, 2H), 8.02-7.98 (m, 1H), 7.21 (d, J=5.8Hz, 1H), 4.86 (dd, J=6.3, 10.5 Hz, 1H), 3.51-3.41 (m, 1H), 3.25-3.16 (m,1H), 2.13-1.85 (m, 4H), 1.66-1.52 (m, 1H) and 1.40-1.20 (m, 1H) ppm.

LCMS RT=1.7 min, (M+H) 375.4.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethylpiperidin-2-one(460)

LCMS RT=2.0 min, (M+H) 389.1.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylazepan-2-one(461)

LCMS RT=2.0 min, (M+H) 389.1.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-ethylazepan-2-one(462)

¹H NMR (300 MHz, d6-DMSO) δ 12.35 (s, 1H), 8.68 (d, J=1.7 Hz, 1H), 8.27(d, J=2.0 Hz, 1H), 8.21 (m, 2H), 7.28 (d, J=6.0 Hz, 1H), 4.98 (dd,J=6.9, 10.7 Hz, 1H), 3.88-3.79 (m, 1H), 3.84 (dd, J=11.4, 15.5 Hz, 1H),3.49-3.17 (m, 5H), 2.08 (d, J=13.1 Hz, 1H), 1.95-1.88 (m, 3H), 1.65-1.58(m, 1H), 1.42 (m, 1H) and 1.04 (t, J=7.0 Hz, 3H) ppm.

LCMS RT=3.3 min, (M+H) 403.4.

(R)-5-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyppyrrolidin-2-one(503)

LCMS RT=2.2 min, (M+H) 361.2.

(S)-3-(5-fluoro-2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one(502).

LCMS RT=2.3 min, (M+H) 409.

(S)-6-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4-(4-methoxybenzyl)-1,4-oxazepan-5-one(505)

LCMS RT=3.1 min, (M+H) 497.7.

The starting amine for this compound was prepared following establishedprocedures as described in: Blizzard, Timothy A.; Chen, Helen Y.; Wu,Jane Yang; Kim, Seongkon; Ha, Sookhee; Mortko, Christopher J.;Variankaval, Narayan; Chiu, Anna. 7-Oxo-2,6-Diazabicyclo[3.2.0]heptane-6-sulfonic acid derivatives as b-lactamaseinhibitors and their preparation, pharmaceutical compositions and use inthe treatment of bacterial infections. PCT Int. Appl. (2008), 101pp.WO2008039420.

(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one(500).

LCMS RT=1.6 min, (M+H) 357.6.

(S)-3-(2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one(501)

LCMS RT=1.6 min, (M+H) 341.4.

3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-7,7-dimethylazepan-2-one(504)

LCMS RT=3.2 min, (M+H) 403.6.

The amine for this compound was prepared following procedures asdescribed in: J. A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routesfor the generation of 7,7-dialkyl-2-azepinones. Tetrahedron Letters(1996), 37(50), 8985-8988

6-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1,4-oxazepan-5-one(513)

A mixture of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,15a, (0.17 g, 0.36 mmol) and (6S)-6-amino-1,4-oxazepan-5-one (0.06 g,0.43 mmol) in DMF (2 mL) with ^(i)Pr₂NEt (0.10 mL, 0.57 mmol) was heatedto 90° C. After 1 hour, the temperature was raised to 100° C. After 24hours, the mixture was heated to 140° C. for 15 min (microwave). Themixture was partitioned between water and EtOAc and the aqueous layerwas extracted with EtOAc twice more. The combined organic phases weredried organic over Na₂SO₄, filtered and concentrated in vacuo. Theresulting crude material (0.16 g) was treated with LiOH (1N solution, 1mL) in THF (3 mL) overnight. LC-MS indicates hydrolysis of amide alongwith detosylation. The mixture was concentrated in vacuo and purified bypreparative HPLC to provide semi pure product (23 mg). This material wassubjected to cyclization conditions without further purification. To aflask was charged with the crude material (0.020 g, 0.051 mmol), EDCI(0.010 g, 0.056 mmol) and HOAt (0.002 g, 0.015 mmol) and DCM (1 mL) wasadded ^(i)Pr₂NEt (0.018 mL, 0.100 mmol) and DMF (0.5 mL). After 1 hour,additional EDCI was added (0.7 eq). After 3.5 hour, the reaction wascomplete and the mixture was concentrated in vacuo. Purification bypreparative HPLC followed by removal of TFA salt by filtration throughbasic resin provided the desired product: LCMS RT=1.9 min, (M+H) 377.5.The starting amine for this compound was prepared following theestablished procedures as described in: J. A. Robl, E. Sieber-McMaster,R. Sulsky Synthetic routes for the generation of7,7-dialkyl-2-azepinones. Tetrahedron Letters (1996), 37(50), 8985-8988.

The following are general procedures for conversion of the cyclohexanecarboxylic acids, 553 or 35a, to carboxamides of type 43a:

Formation of (1S,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-ethylcyclohexanecarboxamide(521)

To a mixture of (1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-1-carboxylicacid, 553, (0.049 g, 0.126 mmol) and HATU (0.056 g, 0.147 mmol) in DMF(1.0 mL) at room temperature was added ethylamine (0.189 mL of 2 Msolution, 0.377 mmol). The mixture was stirred at room temperature untilall starting material had been converted as judged by HPLC. After 45minutes, the mixture was partitioned between aqueous K₂CO₃ and EtOAc andthe organic layer was separated and dried over Na₂SO₄ and concentratedin vacuo. Preparative HPLC provide the desired product as the TFA salt,which was converted to the parent compound by elution through a basicPSA cartridge with MeOH followed by concentration in vacuo. (14 mg, 30%yield).

¹11 NMR (300 MHz, MeOD) δ 8.93 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.3 Hz,1H), 8.18 (s, 1H), 7.99 (d, J=4.0 Hz, 1H), 4.53 (ddd, J=7.1, 11.1 Hz,1H), 3.15-3.02 (m, 2H), 2.43-2.34 (m, 1H), 2.30-2.26 (m, 1H), 1.97-1.82(m, 3H), 1.77-1.65 (m, 2H), 1.47-1.35 (m, 2H) and 0.97 (t, J=7.3 Hz, 3H)ppm.

LCMS RT=2.0 min, (M+H) 417.5.

(1S,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N,N-diethylcyclohexanecarboxamide

LCMS RT=2.26 min, (M+H) 445.58.

Formation ofCis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxamide(544) andCis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N,N-dimethylcyclohexanecarboxamide(543)

To a mixture of cis-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarboxylic acid,554, (0.30 g, 0.77 mmol) in DMF (5 mL) at room temperature was addedpyridine (0.61 g, 0.62 mL, 7.70 mmol) followed by di-tert-butyldicarbonate (0.50 g, 2.31 mmol), and NH₄CO₃H (0.33 g, 4.22 mmol). Themixture was stirred overnight at room temperature. LC-MS indicated thepresence of the desired primary amide as well as the N,N-dimethylamideproduct. A 1 mL aliquot of the reaction solution was acidified with HOAcand diluted with DMSO. Preparative HPLC chromatography provided smallamounts both products.

Primary amide, 544, racemic mixture - (8.6 mg): LCMS RT=1.94 min, (M+H)389.42.

Dimethylamide, 543, racemic mixture—(3.7 mg): LCMS RT=2.52 min, (M+H)417.44.

Formation of (1R,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N,N-diethylcyclohexanecarboxamide(518)

To a mixture of (1R,2S)-2-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-1-carboxylicacid (0.050 g, 0.092 mmol), and HATU (0.045 g, 0.120 mmol) in DMF (1 mL)at room temperature was added N,N-diethylamine (0.138 mL of 2 Msolution, 0.280 mmol). When the reaction appeared complete as judged byHPLC, LiOH (0.4 mL of 1 M solution, 0.4 mmol) in water was added. After6 hours, LiOH (0.4 mL of 1 M, 0.4 mmol) was added again and the mixturewas stirred overnight. The mixture was quenched with aqueous saturatedNH₄Cl solution. Aqueous K₂CO₃ was added and the mixture was extractedwith EtOAc (3×), The combined organic phases were washed with aqueoussaturated NH₄Cl solution, filtered and concentrated in vacuo.Preparative HPLC provided the desired product as the TFA salt which wasconverted to the HCl salt by treatment with HCl in MeOH followed byevaporation of the solvents (12.9 mg, 28% yield).

¹H NMR (300 MHz, MeOD) δ 8.67 (d, J=2.3 Hz, 1H), 8.53 (s, 1H), 8.41 (d,J=2.3 Hz, 1H), 8.35 (d, J=5.5 Hz, 1H), 4.75-4.73 (m, 1H), 3.74-3.58 (m,1H), 3.42 (m, 2H), 3.29-3.22 (m, 2H), 2.57 (m, 1H), 2.09-2.03 (m, 1H),1.96-1.76 (m, 4H), 1.06 (t, J=7.1 Hz, 3H) and 0.94 (t, J=7.1 Hz, 3H)ppm.

LCMS RT=3.3 min, (M+H) 445.6.

(1R,2S)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-ethylcyclohexanecarboxamide(519)

LCMS RT=2.95 min, (M+H) 417.5.

Cis-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-methylcyclohexanecarboxamide(539)—racemic mixture

LCMS RT=2.13 min, (M+H) 403.44.

Formation of5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine(44b)

2Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol) ,5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,44a, (53.0 g, 127.3 mmol) and Na₂CO₃ (40.5 g, 381.9 mmol) were dissolvedin a mixture of DME (795 mL) and water (159 mL). The mixture was purgedwith nitrogen for 20 minutes and treated with Pd(PPh₃)₄ (7.4 g, 6.6mmol). After purging with nitrogen for another 20 minutes, the reactionwas heated to reflux overnight, cooled to room temperature and dilutedwith water (600 mL). The resulting suspension was stirred at roomtemperature for 30 minutes and the precipitate was then collected byfiltration, washed with water and acetonitrile and dried at 50° C. toafford 48.2 g of5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid.

¹H NMR (300 MHz, DMSO-d6) δ 8.70-8.58 (m, 2H), 8.54-8.41 (m, 2H), 8.09(d, J=8.4 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine(44c)

5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine,44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) andtreated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping thetemperature below 20° C. After addition was complete, the reaction wasstirred at room temperature for 2 hours, then treated with anotherportion of m-CPBA (1.9 g) and stirred for another hour. The reactionmixture was washed with 12% aqueuous K₂CO₃ (2×1.0 L) and the organiclayer was dried on Na₂SO₄ and concentrated in vacuo to provide 50 g of5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridineas a yellow solid.

¹H NMR (300 MHz, DMSO-d6) δ 9.11 (d, J=1.5 Hz, 1H), 8.69 (s, 1H), 8.65(dd, J=9.0, 2.9 Hz, 1H), 8.52 (dd, J=2.8, 1.2 Hz, 1H), 8.11 (d, J=8.4Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

Formation of tert-butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate(44d)

5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(1R,3S)-3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF(100 mL). The reaction mixture was heated to 50° C. for 6 hours, thencooled to room temperature. Celite was added and the solvent was removedunder reduced pressure. The Celite-supported residue was purified bysilica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7g of tert-butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate.

¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 8.46-8.41 (m, 1H), 8.29 (d,J=1.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (d, J=3.2 Hz, 1H), 7.27(d, J=8.4 Hz, 2H), 4.91 (d, J=8.0 Hz, 1H), 4.41 (s, 1H), 4.29-4.01 (m,1H), 3.64 (s, 1H), 2.47 (d, J=11.5 Hz, 1H), 2.36 (s, 3H), 2.24 (d,J=13.1 Hz, 1H), 2.08 (d, J=10.9 Hz, 1H), 1.91 (d, J=13.8 Hz, 1H), 1.43(s, 9H), 1.30-1.03 (m, 4H).

Formation of (1S,3R)-N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine(44e)

Tert-butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate,44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) andtreated with trifluoroacetic acid (31 mL). After 5 minutes, thevolatiles were evaporated under reduced pressure, and the resultingresidue was treated with 1N NaOH (75 mL). The resulting precipitate wascollected by filtration, washed with water (3×30 mL) and vacuum dried toprovide 2.7 g of (1S,3R)-N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamineas a white solid.

¹H NMR (300 MHz, MeOD) d 8.56 (dd, J=8.0, 3.9 Hz, 2H), 8.35-8.26 (m,1H), 8.12 (dd, J=10.3, 6.1 Hz, 3H), 7.43 (d, J=8.4 Hz, 2H), 4.36-4.21(m, 1H), 3.28-3.13 (m, 1H), 2.48 (d, J=12.3 Hz, 1H), 2.46 (s, 3H),2.25-1.97 (m, J=17.3, 10.6, 4.1 Hz, 4H), 1.76-1.28 (m, 3H).

Formation of N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide (44f)

(1S,3R)-N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine,44e, (2.3 g, 4.6 mmol) was dissolved in DMF (50 mL) and treated withmorpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6mL, 32.3 mmol). After one hour, the resulting solution was diluted withwater (400 mL) and stirred for an additional two hours. The resultingprecipitate was collected by filtration, washed with water (3×50 mL) anddried to provide the crude product. This material was purified by flashchromatography on a 40 g column using EtOAc/DCM 20-100%, to provide 2.0g of N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamideas a white solid.

¹H NMR (300 MHz, DMSO-d6) δ 8.53-8.43 (m, J=11.9, 2.7 Hz, 3H), 8.22 (d,J=3.9 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 6.32 (d,J=7.5 Hz, 1H), 4.05 (s, J=19.4 Hz, 1H), 3.62 (s, 1H), 3.58-3.45 (m, 4H),3.27-3.18 (m, 4H), 2.36 (s, 3H), 2.12 (d, J=11.7 Hz, 1H), 1.99 (d, J=9.5Hz, 1H), 1.83 (d, J=10.3 Hz, 2H), 1.53-1.11 (m, J=32.3, 22.8, 10.9 Hz,4H).

Formation of N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide(706)

N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide,44f, (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and treatedwith 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol) . Afterstirring for 1 hour, the solvent was evaporated under reduced pressure,and the residue was partitioned between water (100 mL) and ethyl acetate(100 mL). The organic layer was collected, dried on Na₂SO₄ andconcentrated to provide the crude product as a yellow solid. Thismaterial was purified by silica gel chromatography on a 40g column,using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl inether and concentrated to provide 1.5 g of N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-morpholine-4-carboxamideas a white solid.

Formation of (1S,3R)-N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclohexane-1,3-diamine(44e)

To a solution of tert-butyl (1R,3S)-3-(2-fluoro-5-(5-fluoro-1-tosyl-1H-pyrrolo-[2,3-b]pyridin-3-yl)phenylamino)cyclohexylcarbamate,44d, (0.65 g, 1.09 mmol) in methylene chloride (22 mL) was addedhydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol).The reaction was heated to 50° C. and stirred for 6 hours. The mixturewas cooled to room temperature and concentrated in vacuo, producing ayellow solid. The crude residue was purified via silica gelchromatography (25-50% Ethyl Acetate/hexanes gradient). Desiredfractions were combined and concentrated in vacuo to produce 350 mg of44e as a yellow powder.

Synthesis of 1-cyano-N-((1R, 3S)-3-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenylamino)cyclohexyl)cyclopropanecarboxamide (871)

To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527mmol) in THF at room temperature was added HATU (0.200 g, 0.527 mmol)followed by N,N-diisopropylethylamine (0.334 mL, 1.91 mmol). Thesolution was stirred for 10 minutes. (1S,3R)-N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclohexane-1,3-diamine,44e, (0.200 g, 0.584 mmol) was then added and solution stirred at roomtemperature for 4 hours. The mixture was concentrated in vacuo andpurified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) togive 80 mg of 871 as off-white solid.

¹H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H), 8.43(d, J=5.2 Hz, 1H), 8.37 (d, J=1.6 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 4.22(s, 2H), 3.80 (s, 1H), 2.17-1.94 (m, 2H), 1.90-1.71 (m, 2H), 1.71-1.06(m, 8H).

Formation of benzyl (1S, 3R)-3-(4-chlorobutanamido)cyclohexylcarbamate(45a)

To a stirred slurry of benzyl N-[(1S, 3R)-3-aminocyclohexyl]carbamate,18e, (0.97 g, 3.41 mmol) in CH₂Cl₂ (34 mL), was added Et₃N (1.00 mL,7.15 mmol) , followed by 4-chlorobutanoyl chloride (0.40 mL, 3.58 mmol).After stirring at room temperature, the mixture was diluted with CH₂Cl₂,washed with 1N HCl (2×), 1N NaOH (2×), and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give 1.07 g ofthe desired product.

¹H NMR (300 MHz, MeOD) δ 7.33-7.26 (m, 5H), 5.04 (s, 2H), 3.73-3.65 (m,1H), 3.56 (t, J=6.5 Hz, 2H), 3.44 (dq, J=3.9, 15.6 Hz, 1H), 2.33-2.28(m, 2H), 2.11-1.97 (m, 3H), 1.90-1.75 (m, 3H), 1.45-1.28 (m, 1H) and1.18-1.02 (m, 3H) ppm.

Formation of benzyl (1S, 3R)-3-(2-oxopyrrolidin-1-yl)cyclohexylcarbamate(45b)

To a slurry of benzyl (1S,3R)—3-(4-chlorobutanamido)cyclohexylcarbamate, 45a, (0.21 g, 0.58 mmol)in THF (8.2 mL) was added potassium tert-butoxide (0.08 g, 0.69 mmol) atroom temperature. After stirring at room temperature for 25 h, themixture was quenched with aqueous saturated NH₄Cl and extracted withEt₂O (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. Flash chromatography(SiO₂, 0-100% EtOAchexanes, gradient) provided a single fractionconsisting of desired product and a small amount of starting material(168 mg). This material was immediately subjected to deprotectionconditions.

¹H NMR (300 MHz, MeOD) δ 7.33-7.27 (m, 5H), 5.04 (s, 2H), 3.95-3.88 (m,1H), 3.58-3.38 (m, 3H), 2.38-2.28 (m, 2H), 2.11-1.76 (m, 6H), 1.63 (d,J=2.7 Hz, 1H), 1.46-1.34 (m, 3H) and 1.21-1.06 (m, 2H) ppm.

Formation of 1-((1R, 3S)-3-aminocyclohexyl)pyrrolidin-2-one (45c)

A degassed solution of benzyl (1S,3R)-3-(2-oxopyrrolidin-1-yl)cyclohexylcarbamate, 45b, (0.165 g, 0.522mmol) and Pd on C (10% wet, Degussa, 0.050 g, 0.024 mmol) in MeOH (15mL) was placed under H₂ atm (balloon). After 105 min, TLC (10% MeOH-DCM)indicated complete consumption of starting material. H₂ was removed andthe solution filtered and concentrated in vacuo. The crude product wasazeotroped with CH₃CN (2×) to remove any residual MeOH and provided thedesired product (96 mg): FIA (M+H) 183.27

Formation of 1-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one(45d)

A mixture of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine,la, (0.14 g, 0.29 mmol) and 1-((1R,3S)-3-aminocyclohexyl)pyrrolidin-2-one, 45c, (0.10 g, 0.53 mmol) andNa₂CO₃ (0.09 g, 0.88 mmol) freshly ground, in THF (2.25 mL) and CH₃CN(0.45 mL) and heat to 135° C. for 30 min. The mixture was slowly pouredinto 15 mL 1M HCl and extracted with EtOAc (5×). The combined organiclayers were washed with brine, dried over Na₂SO₄ and filtered andconcentrated in vacuo. Flash chromatography (SiO₂, 0-20% MeOHCH₂Cl₂gradient) provided the final product as a sticky residue. Triturationwith CH₃CN provided an off white powder (105 mg) which was impure, butwhich was taken directly to the final deprotection step.

LC/MS Rt=3.90 min, (M+H) 589.49.

Formation of 1-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one(956)

A mixture of partially purified 1-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one,45d, (0.105 g, 0.180 mmol) in CH₃CN (5mL) was treated with HCl (2 mL of4 M, 8.00 mmol) in dioxane at 70° C. After 2H, the mixture was cooled toroom temperature. Then CH₃CN was added and the solid that precipitatedwas triturated with more CH₃CN (3×). Preparative HPLC provided thedesired product as the HCl salt (35 mg).

¹H NMR (300 MHz, MeOD) δ 8.72 (d, J=2.2 Hz, 1H), 8.49 (s, 1H), 8.39 (d,J=2.1 Hz, 1H), 8.29 (d, J=5.5 Hz, 1H), 4.54-4.47 (m, 1H), 4.13 (t,J=11.8 Hz, 1H), 3.57-3.45 (m, 2H), 2.42-2.36 (m, 2H), 2.25 (m, 1H),2.15-2.00 (m, 4H), 1.90-1.59 (m, 4H) and 1.53-1.43 (m, 1H) ppm; LC/MSRT=3.15 min, (M+H) 429.53.

Formation of (1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol(46b) 2Chloro-5-fluoro-N-[(3S,5S)-1-oxaspiro[2.5]octan-5-yl]pyrimidin-4-amine, 46a, (0.19 g, 0.73mmol) was dissolved in water (75 mL) and treated with 30% ammoniumhydroxide (10 mL, 86.0 mmol) . The suspension was heated to 50° C. for 5hrs then allowed to stir at room temperature overnight. The volatileswere evaporated under reduced pressure, and the residue, (1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)cyclohexanol,was taken into the next step without further purification.

Formation of N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]methyl}acetamide(46c)

(1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol,46b, (0.19 g, 0.69 mmol) was dissolved in dichloromethane (15 mL) andtreated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL,1.38 mmol). After 5 minutes, the reaction mixture was diluted into 1NHCl (30 mL), and the aqueous layer was brought to a basic pH by additionof 1N NaOH. The resulting suspension was extracted with dichloromethane(50 mL). The organic layer was dried on Na₂SO₄ and concentrated in vacuoto provide the crude product, which was purified by silica gelchromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg ofN-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclo-hexyl]methyl}acetamideas a white foamy solid.

LCMS RT=2.82 (M+1) 317.33.

Formation of N-{[(1S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]methyl}acetamide(857)

N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]-methyl}-acetamide,46c, (0.2 g, 0.6 mmol) was dissolved in acetonitrile (6 mL) and treatedwith5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.5 g, 1.2 mmol) followed by Pd(PPh₃)₄ (0.07 g, 0.06mmol). Aqueous 2M sodium carbonate (3.0 mL, 6.1 mmol) was added, and thevial was sealed and heated in the microwave to 130° C. for 30 min. Theorganic layer was collected and concentrated in vacuo to provide thecrude product, which was dissolved in DMSO and purified by HPLC using5-70% MeOH/H₂O with 6 mM HCl over 15 minutes to provide afterconcentration 75 mg of N-{[(1S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl]methyl}acetamidehydrochloride as an off-white crystalline solid.

¹H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.22 (s, 1H), 9.03 (d, J=2.4Hz, 1H), 8.71 (d, J=2.1 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.41 (d, J=2.1Hz, 1H), 7.81 (t, J =5.8 Hz, 1H), 4.64 (d, J=8.0 Hz, 1H), 3.16-2.99 (m,2H), 2.09-1.73 (m, 3H), 1.85 (s, 3H), 1.73-1.42 (m, 3H), 1.28 (dd,J=27.5, 10.6 Hz, 2H).; LCMS RT=3.47 (M+1) 433.37

Formation of tert-butyl 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl-amino)ethyl(methyl)carbamate(47b)

In a flask containing (1S,3R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,3-diamine,47a, (0.14 g, 0.39 mmol) in THF/EtOH was added tert-butylN-methyl-N-(2-oxoethyl)carbamate (0.10 g, 0.58 mmol) anddiisopropylethylamine (0.13 mL, 0.77 mmol). The solution was heated at70° C. for 30 min. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) wasadded. The solution was stirred at room temperature for 12 hrs. Thesolution was filtered and the solvent evaporated under reduced pressure.The resulting residue was purified by HPLC using 5-70% MeOH/H₂O with 6mM HCl to provide the desired product.

Formation of (1S, 3R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine(47c)

In a flask containing tert-butyl 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylamino)ethyl(methyl)carbamate,47b, (0.02 g, 0.04 mmol) in dichloromethane/MeOH mixture was added HClin Dioxane (3.86 mL of 4 M solution, 15.44 mmol). The solution wasstirred at room temperature for 12 hrs. The solvent was evaporated underreduced pressure and used without further purification.

Formation of 1-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)-3-methylimidazolidin-2-one(958)

In a flask containing (1S,3R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine,47c, (0.020 g, 0.048 mmol) in DMF was added diisopropylethylamine (0.025mL, 0.144 mmol) and bis(4-nitrophenyl) carbonate (0.016 g, 0.053 mmol).The reaction mixture was stirred at room temperature for 3 hrs. Theresulting residue was purified by HPLC using 5-70% MeOH/H₂O with 6 mMHCl to provide the desired product.

Formation of (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-N-(2-methoxyethyl)cyclohexanecarboxamide(789)

(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarboxylicacid (HCl salt)(0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol),diisopropylethylamine (0.06 g, 0.47mmol) and 2-methoxyethanamine (0.04g, 0.47 mmol) were stirred together in 1 ml each of DMF and CH₃CN atroom temperature overnight. All volatiles were removed with a stream ofnitrogen and heat. The residue was dissolved in methanol andpurification with phase preparatory HPLC with 10-90% MeOH/water (HClmodifier) gave the desired product as the HCl salt.

Formation of(S)-2-chloro-5-fluoro-N-(3-methylenecyclohexyl)pyrimidin-4-amine (49a)

To a suspension of methyl(triphenyl)phosphonium bromide (0.86 g, 2.40mmol) in THF (100 mL) in a flamed dry flask was added(bis(trimethylsilyl)amino)lithium (2.40 mL of 1 M solution, 2.40 mmol)at room temperature. The reaction mixture was allowed to stir at roomtemperature for 1 hr. A solution of(S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanone, 29b, (0.48 g,2.00 mmol) in 20 mL of THF was added. The reaction was allowed to stirat room temperature for 2 hrs. The mixture was quenched by pouring intobrine and the aqueous phase was extracted with EtOAc. The layers wereseparated and the organic was dried over MgSO₄, filtered and evaporatedto dryness. The crude residue was purified via silica gel chromatography(0-100% EtOAc/hexanes gradient) to afford 270 mg of the desired product.

LCMS RT: 3.83 min, (M+1): 242.2.

Formation of 2-chloro-5-fluoro-N-((3R,5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine (49b, 49c)

3-chloroperoxybenzoic acid (0.40 g, 1.79 mmol) was added to a solutionof (S)-2-chloro-5-fluoro-N-(3-methylenecyclohexyl)pyrimidin-4-amine,49a, (0.27 g, 1.12 mmol) in water (0.6 mL) and MeOH (1.5 mL) at roomtemperature. The reaction mixture was allowed to stir at roomtemperature for 1 hr. The mixture was diluted with EtOAc and washed withaqueous saturated NaHCO₃ solution. The organic phase was dried (MgSO₄),filtered and evaporated to dryness. The crude residue was purified viasilica gel chromatography (0-100% EtOAc/hexanes gradient) which yieldedboth diastereomers, 49b and 49c. The isolated upper (less polar) spot,49b, was carried forward.

LCMS RT=3.21 (M+1) 258.2.

Formation of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(methyl-thiomethyl)cyclohexanol(49d)

2-chloro-5-fluoro-N-((3R,5S)-1-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine, 49b, (0.10 g, 0.38mmol) was dissolved in THF (2 mL). Methylsulfanylsodium (0.08 g, 1.15mmol) was added to the reaction and the mixture was allowed to stir atroom temperature for 3 hrs. An additional 36 mg portion ofmethylsulfanylsodium in THF (2 mL) was added and the reaction mixturewas stirred overnight at room temperature. After LCMS showed startingmaterial was still present, the reaction was warmed to 50° C. andstirred for 1 hr. The reaction was quenched with water and diluted withEtOAc. The layers were separated and the organic phase was washed withbrine, dried (MgSO₄), filtered and evaporated to dryness. The cruderesidue was purified via silica gel chromatography (0-100%Etoac/hexanesgradient). The product (contaminated with small amount of staringmaterial) was carried on to the next step without further purification.

LCMS RT=3.56 (M+1) 306.2.

Formation of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol(49e)

To a solution of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol,49d, (0.09 g, 0.28 mmol) in CH₃CN (4 mL) was added5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.14 g, 0.33 mmol) followed by aqueous Na₂CO₃ (0.42 mL of 2 M solution,0.83 mmol). The reaction was degassed with nitrogen for 15 min andtetrakis triphenylphosphinepalladium(0) (0.02 g, 0.01 mmol) was added.The reaction was heated to 140° C. via microwave irradiation for 20minutes. The mixture was cooled to room temperature and was diluted withwater/EtOAc. The layers were separated and the organic phase was washedwith brine, dried over MgSO₄, filtered and evaporated to dryness. Thecrude residue was purified via silica gel chromatography (0-100%EtOAc/hexanes gradient).

¹H NMR (300 MHz, DMSO) δ 8.76 (d, J=1.8 Hz, 1H), 8.47 (d, J=8.1 Hz, 1H),8.30 (t, J=26.7 Hz, 1H), 8.05 (d, J=8.1 Hz, 2H), 7.95-7.45 (m, 2H), 7.43(s, 1H), 4.81 (s, 1H), 4.32-3.84 (m, 1H), 2.70 (d, J=19.5 Hz, 2H), 2.36(s, 2H), 2.14 (s, 1H), 2.13 (s, 1H), 2.14-1.94 (m, 2H), 2.14-1.59 (m,6H), 1.48-0.83 (m, 3H).

Formation of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanol(49f)

To a cold (0° C.) solution of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol,49e, (0.044 g, 0.077 mmol) in CH₂Cl₂ (2 mL) was added3-chloroperoxybenzoic acid (0.034 g, 0.155 mmol). After stirring for 1hour at 0° C., the mixture was diluted with water and CH₂Cl₂.The layerswere separated and the organic was washed with aqueous saturated NaHCO₃soln., dried over MgSO₄, filtered and evaporated to dryness. The cruderesidue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient).

LCMS RT=4.20 (M+1) 608.3.

Formation of (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanol(886)

To a solution of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanol,49f, (0.045 g, 0.074 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25%w/v, 9.255 mmol). The reaction mixture was allowed to stir at roomtemperature for 5 minutes, after which the mixture was quenched with theaddition of aqueous saturated NH₄C₁ solution and then diluted withEtOAc. The layers were separated and the organic was washed with brine,dried over MgSO₄, filtered and evaporated to dryness. The crude residuewas purified via silica gel chromatography (0-10% MeOH/CH₂Cl₂ gradient).

Formation of (R)-1-methylcyclohex-2-enol (50a)

In a 1000 mL flamed-dried round bottom flask, a mixture of (S)-BINAP(6.2 g, 10.0 mmol) and Rh₂(cod)₂Cl₂ (2.1 g, 4.2 mmol) in anhydrous THF(350 mL), was stirred under nitrogen for 30 minutes at room temperature.The homogeneous red reaction mixture was then cooled to 0° C. andcyclohex-2-en-1-one (16.0 g, 166.4 mmol) was added followed by dropwiseaddition of neat trimethylaluminium (12.4 g, 16.5 mL, 166.4 mmol). Themixture was allowed to warm to room temperature for 30 min and thenstirred for 1 hour. The reaction was monitored by NMR and a worked upaliquot indicated complete conversion to tertiary alcohol. When thereaction was complete, its temperature was lowered to 0° C. and quenchedcarefully with aqueous saturated NH₄C₁ solution (500 mL). The layerswere separated and the aqueous phase was further washed with ether(5×100 mL) and the combined organics were dried (MgSO₄) filtered over acelite pad and concentrated in vacuo to a yellow-brownish crude oil.Vacuum distillation (38° C. at 0.5-1 mm Hg), provided 13.9 g (72%) oflight amber color oil.

Formation of (R)-tert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane(50b)

To a solution of (R)-1-methylcyclohex-2-enol, 50a, (1.00 g, 8.91 mmol)in 20 dry DMF at room temperature was added 4H-imidazole (1.82 g, 26.74mmol), tert-butyldimethylchlorosilane (2.02 g, 13.33 mmol) and acatalytic amount of 4-dimethylaminopyridine (0.11 g, 0.89 mmol). Theresulting mixture was stirred at room temperature overnight. It was thendiluted with ether, washed consecutively with water, citric acid andwater. The organic phase was dried with MgSO₄, filtered and concentratedin vacuo. The colorless crude oil 1.98 g was used directly in the nextstep without further purification.

Formation of tent-butyldimethyl((1R, 2R,6R)-2-methyl-7-oxabicyclo[4.1.0]heptan-2-yloxy)silane (50c)

3-chlorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) was added in oneportion to a stirred solution of(R)-tert-butyldimethyl(1-methylcyclohex-2-enyloxy)silane, 50b, (1.98 g,8.87 mmol) and sodium hydrogen carbonate in 30 mL of dry dichloromethaneat room temperature under nitrogen. The resulting mixture was stirredfor 20 hours. Then, 25% sodium sulfite solution (30 mL) was added andthe resulting biphasic mixture was stirred for 15 minutes. The 2 layerswere separated and the aqueous layer was extracted with dichloromethane(2×20 mL). The combined organic phases were washed with aqueoussaturated NaHCO₃. dried (Na₂SO₄) and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-10% EtOAc-hexanesgradient) to provide 647 mg of compound 50c.

Formation of (1R, 2R,3S)-3-azido-1-(tert-butyldimethylsilyloxy)-1-methylcyclo-hexan-2-ol(50d)

To a stirred solution of tert-butyl-dimethyl-[[(1R, 5R,6R)-5-methyl-7-oxabicyclo[4.1.0]heptan-5-yl]oxy] silane, 50c, (0.05 g,2.15 mmol) in methanol (5 mL) and H₂O (0.6 mL) was added NH₄Cl (0.23 g,0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide(0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmedto 60° C., stirred for 12 h, at which point TLC-analysis revealed tracesof the starting material. The reaction mixture was cooled to ambienttemperature, quenched with H₂O (2 mL), concentrated under reducedpressure to remove methanol, extracted with ethyl acetate (3×15 mL),washed with brine (10 mL), dried over MgSO₄, filter and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography (2.5-10% ethyl ether in hexanes gradient) to afford 254mg of (1R, 2S,6R)-2-azido-6-[tert-butyl(dimethyl)silyl]oxy-cyclohexanol, 50d, as aclear oil.

Formation of (1R, 2R,3S)-3-amino-1-(tert-butyldimethylsilyloxy)-1-methylcyclohexan-2-ol (50e)

A solution of azide, 50d, (0.25 g; 0.89 mmol) in 20 mL of ethyl acetatewas hydrogenated with Degussa palladium (20 mole %) under 1 atmosphereof hydrogen overnight. The reaction mixture was filtered over celite andthe celite was eluted with 2×10 mL of EtOAc. The filtrate wasconcentrated in vacuo to afford 230 mg of an oil that was used directlyfor the next step without further purification.

Formation of (1R, 2R,6S)-2-(tert-butyldimethylsilyloxy)-6-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methylcyclohexanol(50f)

To a stirred suspension of (1R, 2R,6S)-6-amino-2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-cyclohexanol, 50e,(0.16 g, 0.62 mmol) in THF (8 mL) in a microwave sealed tube vessel wasadded5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,1a, (0.29 g, 0.63 mmol) followed by N-ethyl-N-isopropyl-propan-2-amine(0.13 mL, 0.74 mmol). The resulting reaction mixture was capped andwarmed to 70° C., stirred for 14 h. The reaction mixture was cooled toambient temperature, added water (2 mL), concentrated under reducedpressure to remove THF. The crude product was diluted with ethyl acetate(25 mL), insoluble material (sulfone la) was removed by filtration. Theorganic layer was separated, washed with brine (2×5 mL), dried overNa₂SO₄, filter and concentrated under reduced pressure. The crudeproduct was purified by silica-gel plug using 10-30% ethyl acetate inhexanes as eluant to afford 350 mg of (1R, 2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol(50f).

Formation of (1R, 2R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-1-methylcyclohexane-1,2-diol(860)

To a stirred solution of (1 R, 2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol,50f, (0.11 g; 0.16 mmol) in THF (2 mL) at room temperature, was addedtetrabutylammonium fluoride (1.5 equiv) and the reaction mixture stirredfor 1.5 h, at which point HPLC-analysis revealed no starting materialbut the de-tosylated product was observed with minor desilylation. Anadditional equivalent of TBAF was added and the reaction mixture wasstirred at room temperature overnight. The reaction mixture wassuspended in ethyl acetate (10 mL), washed with H₂O (2×4 mL), aqueoussaturated NH₄Cl solution (2 mL) and brine (2 mL). The organic phase wasdried (Na₂SO₄) and concentrated in vacuo to provide 139 mg of crude. Thecrude residue was purified by reverse phase HPLC (5-95% MeOH/water w/HC₁buffer over 15 minutes). to afford 15 mg of desired product, 860.

LCMS M+1 =392.34

Formation of ((cyclohex-2-enyloxy)methyl)benzene (51a)

A solution of cyclohex-2-en-1-ol (10.0 g, 101.9 mmol) in anhydrous THF(100 mL) was added to a stirred suspension containing sodium hydride(8.0 g, 199.7 mmol) (60% dispersion in oil) and benzyl bromide inanhydrous THF (250 mL) maintained at 50° C. The resulting solution wasstirred at 55-60° C. for 18 h. After cooling to ambient temperature,water was added to quench the reaction and the mixture was diluted withether (500 mL). The organic phase was separated, dried (Na₂SO₄),filtered and concentrated in vacuo to an oil that was subjected to ashort silica plug filtration to provide 16.1 g of desired product 51athat was used directly in the next step without further purification.

Formation of racemic cis andtrans-1-benzyloxy)-7-oxabicyclo[4.1.0]heptane (51b and 51c)

A solution of benzyl ether 51a (16.10 g, 0.89 mol) in 500 mL of CH₂Cl₂at 0° C. was treated with 77% mCPBA (21.08 g; 0.09 mol) portionwise. Thereaction mixture was stirred at 0° C. for 2 h then at room temperaturefor 12 h. When the reaction is complete, it was quenched with sodiumthiosulfate (100 mL) and the organic phase was further washed withanother 100 mL of sodium thiosulfate, followed by aqueous NaHCO₃solution, 5% NaOH (200 mL) and finally water. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo to afford an oil that waspurified by silica gel chromatography (5% to 20% Et₂O/hexanes) to afford11.44 g of trans-epoxide 51b and 3.95 g of cis-epoxide 51c were isolated(66:34 ratio).

Formation of racemic 1-benzyloxy-3-methoxycyclohexan-2-ol (51d)

A solution of cis-1-benzyloxy)-7-oxabicyclo[4.1.0]heptane, 51c, (2.0 g;9.8 mmol) in 0.2N sulfuric acid (9.8 mmol) in 30 mL of anhydrousmethanol was stirred at room temperature for 30 minutes. The reactionwas diluted with water and extracted with ether. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo to afford 2.31 g of an oil thatwas used directly in the next step without further purification.

Formation of racemic[1-benzyloxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane (51e)

To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol, 51d, (2.31 g,9.78 mmol), tert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66mmol) in 20 dry DMF at room temperature was added 4H-imidazole (1.997 g,29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g,0.98 mmol). The resulting mixture was stirred at room temperatureovernight. It was then diluted with ether, washed with water, aqueoussaturated citric acid solution and water again. The organic phase wasdried with MgSO₄, filtered and concentrated in vacuo. The colorlesscrude oil was used directly in the next step without furtherpurification.

Formation of racemic[1Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane (51f)

A solution of racemic[1-benzyloxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51e,(3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL) andhydrogenated under 45 PSI of hydrogen with Pd-C 10% for 1 h. Thereaction mixture was filtered over a nylon/fiberglass filter to provide,after concentration in vacuo 2.72 g of desired product 51f. Thismaterial was used directly in the next step without furtherpurification.

Formation of racemic[1-Azido-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane (51g)

To a solution of racemic[1Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51f, (2.5g; 9.6 mmol) in 60 mL of dry THF at room temperature was added,triphenylphosphine (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) anddiphenylphosphoryl azide (5.3 g; 19.2 mmol) and the reaction mixture wasstirred at room temperature for 60 h. The solvent was concentrated invacuo and the resultant oil was purified by silica gel chromatography(10% Et₂O-Hexane to ether gradient) to afford 2.57 g of the desiredproduct 51g.

Formation of racemic[1-Amino-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane (51h)

A solution of racemic[1-Azido-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51 g,(2.57 g; 6.3 mmol) in 20 mL of ethyl acetate was hydrogenated with Pd-C10% (5 mole %; Degussa) at 45 PSI in a Parr hydrogenation apparatus for1 h. The reaction mixture was filtered over a nylon and glass fiberfilter and concentrated in vacuo to provide 2.32 g of the desiredproduct 51h as a white solid.

Formation of racemicN-((1-2-(tert-butyldimethylsilyloxy)-3-methoxycyclohexyl)-2-chloro-5-fluoropyrimidin-4-amine(51i)

In a flask was placed racemic[1-Amino-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51h, (2.32g; 6.26 mmol). To this was added MeCN and IPA (1.5:1 v/v) to a totalvolume of 125 mL. To the solution was added dipotassium carbonate (4.32g, 31.30 mmol) and the mixt ure was allowed to stir 30 minutes at roomtemperature (to remove any water that might be present). To this mixturewas added 2, 4-dichloro-5-fluoro-pyrimidine (3.14 g, 18.78 mmol) and themixture was stirred at room temperature for 60 h. The reaction wasfiltered thru celite and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (20-100% Ether/hexanes gradient)to afford 2.27 g pure racemate compound 51i.

Formation of (1R, 2S,6R)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-6-methoxy-cyclohexanol(51j)

To a solution of compound racemicN-((1-2-(tert-butyldimethylsilyloxy)-3-methoxycyclohexyl)-2-chloro-5-fluoropyrimidin-4-amine,51i, (1.96 g, 5.03 mmol) in 30 mL of MeOH was added p-TsOH (1.73 g;10.06 mmol). The reaction mixture was stirred at room temperature for 3h and then was concentrated to dryness. The residue was dissolved inEtOAc (125 mL) and washed with aqueous potassium carbonate 1M (2×50 mL),then brine. The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo to give, after SFC enantiomers separation (50%EtOH-50% CO₂; 10 mL/min; 100 bar) 635 mg of chiral alcohol 51j as awhite solid.

Formation of (1R, 2S,6R)-2-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-6-methoxycyclohexanol(51k)

In a microwave tube was placed5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.10 g, 0.23 mmol). To this was added acetonitrile (0.61 mL) and thesolution was deoxygenated with nitrogen. To the reaction was added (1R,2S, 6R)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-6-methoxy-cyclohexanol,51j, (0.04 g, 0.14 mmol) and palladium catalyst (24 mg), and thenaqueous sodium carbonate (0.21 mL of 2 M solution, 0.41 mmol). Thereaction was sealed and heated to 120° C. in the microwave reactor for15 min. The reaction was diluted with ethyl acetate (40 mL), filteredthru florisil, and concentrated in vacuo to give crude as a green solid.This was purified by silica gel chromatography (20-75% EtOAc/hexanesgradient). Used resulting product directly in the next step.

LCMS (M+1) =546.35.

Formation of (1R, 2S,6R)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-6-methoxycyclohexanol(831)

In a microwave vial was placed azaindole 51k (0.050 g; 0.092 mmol). Tothis was added 3 mL of THF and 0.9 mL of 0.8 M LiOH. The vial was sealedand heated to 120° C. for 15 minutes in the microwave. When the reactionis complete, it was neutralized with 9 equivalents of 1N HCl (0.704 mL),then aqueous saturated NaHCO₃ solution was added and the organic phasewas separated and loaded onto silica gel for purification and elutedw/2% MeOH to 12% gradient over 10 minutes (4 g column) to provide 34.5mg (91%) desired product 831.

Formation of 1-methylcyclohex-3-ene-1-carboxylic acid (52a)

N-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5M solution in hexanes, 436.0 mmol) at −78° C. The resulting solution wasstirred for 30 minutes at −78° C. To the reaction was then addedcyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) and the reactionwas allowed to warm to 60° C. for 2 hrs. The reaction was cooled to roomtemp and iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and thereaction was allowed to stir overnight and then quenched with 1 N HCluntil the pH<4. The crude product was extracted into CH₂Cl₂ and water.The organic phase was concentrated in vacuo to a yellow oil (27 g) andused without further purification.

MS/RT: 141.09 (M+H)/1.65

Formation of 1-methylcyclohex-3-ene-1-carboxamide (52b)

To a solution of 1-methylcyclohex-3-ene-1-carboxylic acid, 52a, (54.0 g,385.2 mmol) dissolved in CH₂Cl₂ (200 mL) was added thionyl chloride(56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to refluxfor 3 hrs, then cooled and concentrated in vacuo. The residue wasredissolved in 200 mL of CH₂Cl₂.To the reaction was added ammoniumhydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction wasstirred overnight. The reaction was extracted into CH₂Cl₂ and water. Theorganic phase was concentrated in vacuo and purified via flash silicagel chromatography (EtOAc), yielding 25 g of1-methylcyclohex-3-ene-1-carboxamide.

MS/RT: 139.96 (M+H)/2.66

Formation of 4-iodo-1-methyl-6-azabicyclo [3.2.1]octan-7-one (52c)

A solution of 1-methylcyclohex-3-ene-1-carboxamide, 52b, (5.0 g, 35.9mmol) dissolved in 100 mL of pentane and CH₂Cl₂ was cooled to 0° C. andtreated with triethylamine (11.0 mL, 79.0 mmol) andtrimethylsilyl-triflate (14.3 mL, 79.0 mmol) sequentially. The resultingmixture was stirred for 1 hour at room temperature. The lower layer wasremoved via pipette. The upper pentane layer was concentrated in vacuoand the resulting residue was dissolved in THF (100 mL). To the stirredreaction was added iodine (20.1 g, 79.02 mmol) and the reaction wasallowed to stir overnight at room temperature. After quenching withNa₂SO₃ and NaHCO₃, the reaction was partitioned between CH₂Cl₂ andwater. The organic layers were combined, dried over Na₂SO₄, concentratedin vacuo to a dark yellow oil (9.5 g) that was used without furtherpurification.

MS/RT: 266.06(M+H)/2.39

Formation of tent butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (52d)

To a solution of 4-iodo-1-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c,(9.5 g, 35.8 mmol) in CH₂Cl₂ (100 mL) was added DMAP (0.2 g, 1.8 mmol),triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butylcarbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at roomtemperature. The product was extracted into CH₂Cl₂ and water. Theorganic layer was concentrated in vacuo and the residue was purified viasilica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g.

MS/RT: 366.06 (M+H)/3.95

Formation of tert butyl4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (52e).

To a solution of tert-butyl4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate, 52d, (7.6g, 20.8 mmol) in 100 mL of toluene was added1,8-diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.6 mmol). The reaction waswarmed to reflux and stirred overnight. The reaction was concentrated invacuo and the resulting residue was purified by silica gelchromatography (4:1 Hexanes:EtOAc), yielding 4.9 g of the desiredproduct, 52e.

MS/RT: 238.14 (M+H)/3.33

Formation of methyl5-(tert-butoxycarbonylamino)-1-methylcyclohex-3-enecarboxylate (52f)

To a solution of tert-butyl1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate, 52e, (4.93 g,20.78 mmol) in MeOH (100 mL) was added cesium carbonate (13.54 g, 41.56mmol). The reaction was stirred overnight and then concentrated invacuo. The cesium salts were precipitated with Et₂O and filtered. Theether filtrate was evaporated to give 5.5 g of a yellow oil that wasused without further purification.

MS/RT: 270.17 (M+H)/3.64

Formation of methyl5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate (52g)

Methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohex-3-enecarboxylate,52f, (5.59 g, 20.75 mmol) was dissolved in 100 mL of MeOH. To thestirred solution was added 5% palladium on carbon (1.11 g, 10.38 mmol)and the reaction was stirred under a hydrogen balloon for 2 days. Thereaction was filtered through celite, and the filtrate was concentratedin vacuo and used without further purification.

MS/RT: 272.24(M+H)/3.62

Isolation of (1R, 3S)-methyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methyl-cyclohexanecarboxylate(52h).

A stirred solution of methyl5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes.The resulting solution was stirred at room temperature for 1 hour, thenconcentrated to dryness and redissolved in THF (50 mL). To the reactionmixture was added ^(i)Pr₂NEt (10.84 mL, 62.25 mmol) and2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. Thereaction was stirred at reflux overnight, concentrated in vacuo andresulting residue was purified by silica gel chromatography (1:1Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil.300 mg of the racemic methyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylatewas submitted for SFC chiral separation, yielding 100 mg of the desiredproduct, 52 h, as a yellow oil.

MS/RT: 302.16 (M+H)/3.68

Formation of (1R, 3S)-methyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate(52i).

In a 25 mL round-bottomed flask were combined (1R, 3S)-methyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate,52 h, (0.061 g, 0.202 mmol) ,5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol) , disodium carbonate (0.064g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixturewas degassed via a stream of nitrogen. To the reaction was addedtetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) and thereaction was stirred at reflux overnight. The reaction was concentratedin vacuo and purified by silica gel chromatography (4:1 Hexanes:EtOAc),yielding 85 mg of desired product, 52i.

MS/RT: 572.33 (M+H)/6.27

Formation of (1R, 3S)-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate(52j)

To a stirred solution of (1R, 3S)-methyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate,52i, (0.085 g, 0.149 mmol) in 10 mL of MeOH was added NaH (0.004 g,0.178 mmol) at room temperature. The resulting suspension was stirredfor 2 hrs, quenched with solid NH₄C₁. The mixture was concentrated invacuo and purified via silica gel chromatography (3:1 Hexane:EtOAc),yielding 55 mg of the desired product, 52j.

MS/RT: 418.32 (M+H)/3.30

(1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylicacid (826)

To a solution of (1R, 3S)-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate,52j, (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) wasadded LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2days at room temperature and then concentrated to dryness. The residuewas washed with ethanol. The combined ethanol washings were concentratedin vacuo, yielding 30 mg of desired product as an off white solid.

¹H NMR: (300 MHz, DMSO) δ 12.34 (s, H), 8.74 (d, J=2.3 Hz, H), 8.33 (d,J=2.3 Hz, H), 8.28 (d, J=1.6 Hz, H), 8.17-8.12 (m, H), 4.34 (s, H), 4.29(s, H), 3.89 (s, H), 3.55 (d, J=6.3 Hz, H), 3.32 (s, H), 2.50 (s, H),2.29 (s, H), 1.95-1.90 (m, H), 1.82 (d, J=6.6 Hz, H), 1.76 (s, 3 H),1.67 (s, H), 1.55 (s, H), 1.44-1.42 (m, H), 1.31 (s, H), 1.23 (s, H),1.17 (s, H), 1.07 (s, H), 0.84 (d, J=6.9 Hz, H) and -0.00 (d, J=1.0 Hz,H) ppm; MS/RT: 404.24 (M+H)/3.39.

Formation of (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxamide(924)

(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylicacid, 826, (0.050 g, 0.108 mmol),benzotriazol-1-yl-[bis(dimethylamino)methylene]oxoniumhexafluorophosphate (0.081 g, 0.216 mmol) andN-ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) were combinedin 5 mL of THF. To the reaction was then added ammonia hydrochloride(0.002 g, 0.032 mmol) and the reaction was allowed to stir overnight atroom temperature. After concentration under reduced pressure, themixture was purified by reverse phase HPLC chromatography, yielding 3.3mg of desired product.

¹H NMR (300 MHz, MeOD) δ 8.85 (d, J=2.4 Hz, H), 8.22 (d, J=2.3 Hz, H),8.16 (s, H), 7.99 (d, J=4.1 Hz, H), 7.86 (s, H), 3.48 (d, J=7.0 Hz, H),2.80 (s, H), 2.15 (s, H), 2.0 (s, H), 1.86 (qn, J=3.3 Hz, H), 1.80 (s, 3H), 1.74 (m, 2 H), 1.44 (s, 6H); LC/MS: 403.34 (M+H), RT=1.77.

Formation of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-isocyanato-3-methylcyclohexyl)pyrimidin-4-amine (52m).

To a solution of (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylicacid, 826, (0.100 g, 0.216 mmol) and(azido(phenoxy)phosphoryl)oxybenzene (0.093 mL, 0.432 mmol) in 10 mL oftoluene was added 1 mL of N-ethyl-N-isopropyl-propan-2-amine. Thereaction was warmed to reflux overnight. The mixture was concentrated todryness and the residue was purified by silica gel chromatography(EtOAc), yielding 40 mg of desired product as a white foam.

MS/RT: 401.23 (M+H)/3.89

Formation of N-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexyl)pyrrolidine-1-carboxamide(926).

A solution of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-isocyanato-3-methylcyclohexyl)pyrimidin-4-amine, 52m, (0.035 g,0.087 mmol) in 3 mL of NMP with 0.5 mL of pyrrolidine was warmed to 200°C. in a microwave for 30 minutes. The reaction was then concentrated invacuo and purified by reverse phase HPLC chromatography, yielding 8.7 mgof desired product as a tan solid.

¹H NMR: (300.0 MHz, MeOD) δ 8.76 (d, J=2.4 Hz, H), 8.44-8.38 (m, 2 H),8.27 (d, J=5.6 Hz, H), 4.87 (d, J=5.1 Hz, H), 4.64-4.56 (m, 4 H),3.38-3.19 (m, 2 H), 2.65 (s, 2 H), 2.46 (m, H), 2.42 (s, 3 H), 2.16 (s,H), 2.07 (t, J=12.0 Hz, H), 2.00 (s, H), 1.88 (q, J=6.6 Hz, H), 1.88 (s,H), 1.70 (s, H) and 1.61 (d, J=12.8 Hz, H) ppm; MS/RT: 472.38.

Formation of (+/−)-2,3-Trans-methyl3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate (53a)

This compound was prepared as a mixture of trans isomers(endo:exo=84:16) following literature procedures described in: Chang,Linda L.; Truong, Quang; Doss, George A.; MacCoss, Malcolm; Lyons,Kathryn; McCauley, Ermengilda; Mumford, Richard; Forrest, Gail; Vincent,Stella; Schmidt, John A.; Hagmann, William K. Bioorg. Med. Chem. Lett.2007, 17(3), 597-601.

Formation of (+/−)-2,3-Trans-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (53b)

A mixture of (+/−)-2,3-trans-methyl3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate, 53a, (0.32 g, 1.62 mmol)and PdC (10%) in MeOH was purged and placed under H₂ atm (50 PSI) andshaken overnight. The mixture was filtered through celite, concentratedin vacuo and azeotroped twice with CH₃CN to remove traces of MeOH.

¹H NMR of the crude mixture indicated the presence of both the endo andexo products (84:16=endo:exo) which were taken directly into the nextreaction without further purification.

Formation of (+/−)-2,3-Trans-methyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53c)

A mixture of5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,la, (0.46 g, 1.00 mmol) and (+/−)-trans-methyl3-aminobicyclo[2.2.1]heptane-2-carboxylate, 53b, (0.27 g, 1.60 mmol)(84:16=endo:exo) and freshly ground Na₂CO₃ (0.32 g, 2.99 mmol in THF(3.7 mL) and CH₃CN (1.2 mL) was heated to 120° C. for 20 min inmicrowave. The reaction mixture was filtered and the solid was rinsedwith Et₂O and THF. The organic layer was concentrated in vacuo toprovide crude product which was purified by silica gel chromatography(0-40% EtOAc/hexanes, gradient) to provide the desired product (352 mg)as an inseparable mixture of trans-endo and trans-exo isomers(endo:exo=85:15) as indicated by NMR.

LC/MS R_(t)=6.13 min, (M+H) 570.34.

(+/−)-2,3-trans-endo-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53d) & (+/−)-2,3-trans-exo-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53d)

To a solution of trans-endo- and trans-exo-methyl3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate,53c, (0.18 g, 0.31 mmol) in MeOH (3 mL) and CH₂Cl₂ (1 mL) was addedNaOMe (3 mL of 25% w/v, 13.88 mmol). After 90 sec, NH₄Cl solution (5 mL)was added to quench the reaction. The mixture was partitioned betweenaqueous NH₄Cl (half saturated) and EtOAc. The aqueous layer wasextracted again and the combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. Flashchromatography (SiO₂, 0-15% MeOH-DCM, gradient) gave the desiredproducts as a mixture. (white solid): 112 mg ¹H NMR indicated desiredproduct existed as a mixture of endo and exo isomers (endo:exo=84:16)which was taken forward into the hydrolysis step.

(+/−)-2,3-Trans-exo-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53d): minor isomer (exo): LC/MS (method: m117) R_(t)=3.17 min, (M+H)416.27.

(+/−)-2,3-Trans-endo-methyl3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53d): major isomer (endo): LC/MS (method: m117) R_(t)=3.49 min, (M+H)416.27.

(946)(+/−)-2,3-trans-endo-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylicacid & (947)(+/−)-2,3-trans-exo-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylicacid

To a stirred solution of starting methyl esters, 53d, (0.076 g, 0.183mmol) (84:16=endo:exo) in THF (0.60 mL) and MeOH (0.10 mL), was addedNaOH (0.10 mL of 2 M, 0.201 mmol). The reaction progress was monitoredby TLC. After 30 min, additional NaOH (0.18 mL of 2 M solution, 0.37mmol) and MeOH (0.18 mL) was added. The mixture was stirred at roomtemperature for a further 16 hours. The mixture was neutralized with HCl(1M) and concentrated in vacuo. Purification by preparative HPLCprovided 52 mg of the major isomer (946) and 11 mg of the minor isomer(947) as the hydrochloric acid salts.

(946) major (endo) isomer: ¹H NMR (300 MHz, MeOD) δ 8.82 (d, J=2.2 Hz,1H), 8.48 (s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.31 (d, J=5.6 Hz, 1H), 5.11(m, 1H), 2.85 (br s, 1H), 2.68 (br s, 1H), 2.62 (d, J=4.8 Hz, 1H), 1.92(d, J=10.1 Hz, 1H) and 1.77-1.51 (m, 5H) ppm; LC/MS R_(t)=3.51, (M+H)402.32.

(947) minor (exo) isomer: ¹H NMR (300 MHz, MeOD) δ 8.87 (d, J=2.1 Hz,1H), 8.48 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.30 (d, J=5.7 Hz, 1H), 4.73(d, J=3.3 Hz, 1H), 3.12 (m, 1H), 2.76 (br s, 1H), 2.56 (d, J=4.2 Hz,1H), 1.86 (d, J=9.5 Hz, 2H), 1.79-1.49 (complex m, 2H) and 1.51(embedded d, J=10.4 Hz, 2H) ppm; LC/MS R_(t)=3.42, (M+H) 402.32.

(1184)(2S,3S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Compound 1184 was made in a similar fashion as described above forcompounds 946 and 947.

(1070)(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Compound 1070 was made in a similar fashion as described above forcompounds 946 and 947.

Formation of benzyl (1S, 3R)-3-cyanocyclohexylcarbamate (54a)

A suspension of benzyl N-[(1S, 3R)-3-carbamoylcyclohexyl]carbamate, 18d,(0.69 g, 2.50 mmol) in DMF (10 mL) at 0° C. was treated with 2, 4,6-trichloro-1, 3, 5-triazine (0.61 g, 3.29 mmol) and allowed to stirwhile slowly warming to room temperature. After 20 minutes, the solutionbecame gold in color. After 1 hour a precipitate had formed. Stirred foran additional 3 hours then quenched with ice water (100 mL) andextracted with CH₂Cl₂ (2×125 mL) then washed with 1N HCl (100 mL). Theorganic layer was concentrated in vacuo to afford an 730 mg of a residuethat was purified using a pad of silica gel (45 mL) using 30%EtOAc/hexanes as eluent to afford 621 mg of a white solid after vacuumdrying.

¹H NMR (300 MHz, CDCl₃) δ 7.45-7.30 (m, 5H), 5.09 (s, 2H), 4.67 (s, 1H),3.49 (s, 1H), 2.66-2.32 (m, 2H), 2.16-1.79 (m, 3H), 1.52-1.03 (m, 4H).

Preparation of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile(54b)

Benzyl N-[(1S, 3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) wasdissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman'scatalyst (50% wet by weight). The suspension was degassed with hydrogenfor 2 min then placed under static hydrogen atmosphere. After 135 min,TLC showed no remaining starting material. The suspension was filteredthrough celite, washed with THF and degassed with nitrogen followed bythe addition of ^(i)Pr₂NEt (0.21 mL, 1.23 mmol) and5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,la, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at45° C. then concentrated to dryness, absorbed on silica-gel and purifiedby silica gel chromatography using 0-60% EtOAc/hexanes gradient toafford 293 mg of a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, J=2.4 Hz, 1H), 8.49 (s, 1H), 8.39 (d,J=2.4 Hz, 1H), 8.15-8.05 (m, 3H), 7.37-7.23 (m, 2H), 5.01 (d, J=6.2 Hz,1H), 4.13 (s, 1H), 2.75 (d, J=23.0 Hz, 1H), 2.58 (s, 1H), 2.38 (s, 3H),2.20 (d, J=9.1 Hz, 2H), 2.03 (d, J=7.8 Hz, 1H), 1.78-1.43 (m, 4H), 1.26(s, 1H).

Preparation of (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile(54c)

(1R, 3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo [2,3-b]pyridin-3—yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarbonitrile, 54b, (0.29g, 0.55 mmol) was suspended in MeOH (15 mL) and sodium metal added andthe mixture heated at 45° C. The sodium dissolved in advance of thecompound. The mixture was allowed to stir until complete by TLC andLCMS. Concentrated to reduced volume then quenched with 1:1 aqueoussaturated NH₄C₁:water mixture (1 ml) then concentrated to dryness. Theresidue was diluted with EtOAc and washed with water and brine. Theorganic layer was concentrated in vacuo to give 0.3 g of a yellow solidthat was adsorbed on silica-gel and purified using 40g isco column withthe following gradient using 20% MeOH:DCM as the eluent: 0-25%/6 minhold 4 min; 25-50%/4 min hold 9 min to give 146 mg of a white solid.LCMS (10-90% MeOH:water with formic acid).

LCMS RT 4.01 ES+371, ES-369.

Preparation of (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxamide(847)

A sample of (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarbonitrilewas treated with 4N HCl/dioxane and heated at 78° C. overnight.Concentrated to dryness then quenched with aqueous saturated sodiumbicarbonate and CH₂Cl₂ were added to give a slurry. Filtered andextracted with CH₂Cl₂.The organic phase was dried over Na₂SO₄ andconcentrated in vacuo to give 189 mg of an orange residue that waspurified by silica gel chromatography (0-10% MeOH:CH₂Cl₂ gradient) toafford 9.9 mg of a solid: LCMS (10-90% MeOH:water with formic acid): RT3.79 min ES+389.

Preparation of N-((1S,3R)-3-(1H-tetrazol-5-yl)cyclohexyl)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(855)

A suspension of dibutyl(oxo)tin (0.016 g, 0.064 mmol) and (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-carbonitrile(54c) (0.043 g, 0.107 mmol) in toluene (3 mL) was treated withazido(trimethyl)silane (0.200 mL, 1.507 mmol). The mixture was heated ina sealed tube at 120° C. overnight. The mixture was absorbed ontosilica-gel and purified by silica gel chromatography (25-50% gradient of20%MeOH:DCM containing 0.5% AcOH modifier). The combined fractions wereconcentrated to dryness to give a residue that was triturated with etherthen dried under vacuum at 45° C. to afford 44mg of a yellow solid.

¹H NMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (d, J=2.4 Hz, 1H),8.41-8.04 (m, 3H), 7.62 (d, J=7.4 Hz, 1H), 4.30 (s, 1H), 3.54-3.06 (m,3H), 2.67-2.31 (m, 1H), 2.23-1.33 (m, 6H).

Formation of(S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)cyclohexanoneoxime (55a)

To solution of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone(0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylaminehydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred atroom temperature overnight. Then the mixture was warmed to 70° C. for 15min. The reaction mixture was concentrated in vacuo, suspended inEtOAc-DCM, washed with half saturated brine (2×) and filtered through aSiO₂ plug. The resulting residue was azeotroped with CH₃CN (2×) toprovide an off white powder which was used without further purification.

¹11 NMR (300 MHz, MeOD) δ 8.78 (d, J=2.4 Hz, 1H), 8.51 (d, J=10.8 Hz,1H), 8.32 (d, J=2.3 Hz, 1H), 8.10-8.04 (m, 3H), 7.38 (d, J=8.2 Hz, 2H),4.29-4.15 (m, 1H), 3.79-3.74 (m, 0.6H), 2.41 (m, 1H), 2.38 (s, 3H),2.30-2.16 (m, 2H), 2.06-1.84 (m, 4H) and 1.66-1.59 (m, 2H) ppm; LC/MS(method: m120) R_(t)=3.90 min, (M+H) 529.44.

2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine(55c) and2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3S)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine(55b):

To a stirred solution of(S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanoneoxime (0.20 g, 0.38 mmol) and HCl (0.19 mL of 6 M, 1.134 mmol) in MeOH(10 mL) was added (5-ethyl-2-methyl-pyridinium borane (0.12 mL, 0.76mmol) at room temperature. After 30 min, the reaction was quenched withNaHCO₃. The mixture was extracted successively with Et₂O, EtOAc, CH₂Cl₂and EtOAc. Each organic portion was washed with brine and the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. Flash chromatography (SiO₂, 20-100% EtOAc-hexanes) provided thecis-4 (74 mg) and trans-3 (64 mg) isomers.

2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3S)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine(stereoisomer -3)

¹H NMR (300 MHz, MeOD) δ 8.83 (d, J=2.4 Hz, 1H), 8.50 (s, 1H), 8.33 (d,J=2.4 Hz, 1H), 8.07-8.04 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.24-4.17 (m,1H), 3.07-3.00 (m, 1H), 2.34 (m, 1H), 2.14-2.08 (m, 1H), 1.93 (t, J=3.5Hz, 2H), 1.66-1.53 (m, 1H) and 1.44-1.12 (m, 3H) ppm; LC/MS RT=3.64 min,(M+H) 531.47.

2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine(stereoisomer -4)

¹H NMR (300 MHz, MeOD) δ 8.84 (d, J=2.4 Hz, 1H), 8.53 (s, 1H), 8.32 (d,J=2.4 Hz, 1H), 8.07-8.04 (m, 1H), 7.37 (d, J=8.2 Hz, 1H), 4.58-4.54 (m,1H), 3.26-3.23 (m, 1H), 2.38 (s, 3H), 1.98-1.83 (m, 4H) and 1.69-1.60(m, 4H) ppm; LC/MS RT=3.67 min, (M+H) 531.47.

2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl-amino)cyclohexyl)-1,2,4-oxadiazolidine-3,5-dione(796)

To a solution of2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((1S,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136mmol) in THF (2 mL) at 0° C. was added N-(oxomethylene)carbamoylchloride (0.014 mL, 0.176 mmol). A white solid formed immediately. Theslurry was shaken and sonicated to make an even suspension/slurry. Then,CH₂Cl₂ (1 mL)) was added to help solvate the slurry. After 135 min, themixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixturewas quenched with saturated NH₄Cl and acidified with 1M HCl. The mixturewas extracted with EtOAc (3×) and the combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. Preparative HPLCprovided the desired product (25 mg).

¹H NMR (300 MHz, MeOD) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.31(br s, 1H), 4.34 (m, 1H), 2.60-2.56 (m, 1H), 2.27 (m, 1H), 2.08 (m, 3H)and 1.89-1.78 (m, 3H) ppm; LC/MS RT=3.12 min, (M+H) 446.45.

2-((1S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)-1,2,4-oxadiazolidine-3,5-dione(798)

¹H NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.31(br s, 1H), 4.47 (m, 1H), 4.21 (m, 1H), 2.41 (m, 1H), 2.22 (m, 1H),2.10-1.90 (m, 3H), 1.72 (m, 2H) and 1.50 (m, 1H) ppm; LC/MS RT=3.37 min,(M+H) 446.34.

Formation of (S)-dimethyl(3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)methylphosphonate(56a)

To a solution of 2-[5-chloro-1-(p-tolylsul fonyl)pyrrolo [5,4-b]pyridin-3-yl]-5-fluoro-N-[(3 S)-3-piperidyl]pyrimidin-4-amine, 1c,(2.00 g, 3.99 mmol) in dry toluene was added 4 angstrom molecular sievesand methoxyphosphonoyloxymethane (0.97 g, 0.81 mL, 8.78 mmol). Whilestirring under nitrogen, paraformaldehyde (0.90 g, 9.98 mmol) was addedportionwise. The mixture was heated at 90° C. for 90 minutes. Thereaction was cooled to room temperature, diluted with aqueous saturatedNaHCO₃ solution, extracted twice with EtOAc. The combined organic phaseswere dried (MgSO₄), filtered and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography using 0-10%MeOH/CH₂Cl₂ gradient to afford 2.0 g of desired product. LCMS RT=4.47(M+H) 623.3.

Formation of (S)-dimethyl(3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-1-yl)methylphosphonate(690)

To a solution of2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-N-[3S)-1-(dimethoxyphosphorylmethyl)-3-piperidyl]-5-fluoro-pyrimidin-4-amine,56a, (1.00 g, 1.61 mmol) in MeOH (40 mL) was added sodium methanolate(20 mL of 25% w/v, 92.55 mmol) and the reaction mixture was stirred atroom temperature for 30 minutes. All volatiles were removed at reducedpressure and the resulting residue was diluted with aqueous saturatedNH₄Cl solution and extracted twice with CH₂Cl₂.The combined organicphases were dried (MgSO₄), filtered and concentrated in vacuo. Theresulting residue was purified via silica gel chromatography using 0-10%MeOH:CH₂Cl₂ gradient to provide 270 mg of a white solid.

¹H NMR (300.0 MHz, DMSO) δ 12.33 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.28(d, J=2.4 Hz, 1H), 8.20 (d, J=2.6 Hz, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.35(d, J=7.8 Hz, 1H), 4.27-4.17 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H),3.21-3.16 (m, 1H), 2.96-2.90 (m, 3H), 2.33-2.20 (m, 2H), 1.99-1.94 (m,1H), 1.80-1.60 (m, 2H) and 1.47-1.35 (m, 1H) ppm; LCMS RT=3.84 (M+1)469.47.

Formation of((S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)piperidine-1-carboximidamide(57a)

To a solution of pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80mmol) and2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine,lc, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added ^(i)Pr₂NEt (0.14 mL,0.80 mmol). The reaction mixture was stirred at room temperature for 4hours. The mixture was diluted into water, filtered, washed withadditional water, then ether. The filtrate was concentrated in vacuo.The resulting residue was purified by silica gel chromatography using5-20% MeOH/CH₂Cl₂ gradient (product elutes with 20% MeOH) to afford 190mg of the desired product.

¹11 NMR (300 MHz, DMSO) δ 8.73 (d, J=2.2 Hz, 1H), 8.50-8.45 (m, 2H),8.33 (d, J=3.7 Hz, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.0 Hz, 1H),7.53-7.42 (m, J=9.0 Hz, 6H), 3.87 (d, J=13.6 Hz, 1H), 3.17 (d, J=5.2 Hz,1H), 3.03 (q, J=10.9 Hz, 2H), 2.36 (s, 3H), 2.11 (d, J=9.9 Hz, 1H), 1.90(d, J=12.6 Hz, 1H), 1.68 (dd, J=24.5, 13.9 Hz, 2H); LCMS RT=3.07 (M+1)543.34.

Formation of(S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidine-1-carboximidamide(881)

To a solution of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxamidine,57b, (0.18 g, 0.32 mmol) in MeOH (5 mL) was added sodium methanolate (3mL of 25% w/v, 13.88 mmol) and the reaction was stirred at roomtemperature. After 5 min, the mixture was concentrated in vacuo to lightyellow solid. The crude residue was purified via preparatory HPLC(MeOH/1% aqueous HCl) to afford the desired product.

¹H NMR (300 MHz, DMSO) δ 12.79 (s, 1H), 8.77 (s, 1H), 8.60 (d, J=2.3 Hz,1H), 8.43 (d, J=4.8 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H), 7.52 (s, 3H), 4.29(s, 1H), 4.08 (d, J=12.6 Hz, 1H), 3.90 (d, J=13.7 Hz, 1H), 3.16-2.95 (m,2H), 2.17 (d, J=9.7 Hz, 1H), 1.92 (d, J=8.5 Hz, 1H), 1.81-1.57 (m, 2H);LCMS RT=2.03 (M+1) 389.27.

Formation of(3S)-1-allyl-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol (58a)

To a solution of(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b,(0.60 g, 2.46 mmol) and 3-bromoprop-1-ene (0.43 mL, 4.92 mmol) in DMFwas added Zn dust (0.32 g, 4.92 mmol). The reaction was stirred at roomtemperature for 3 days. The mixture was diluted into aqueous saturatedNH₄Cl solution, extracted twice with EtOAc. The combined organic phaseswere washed twice with brine, dried (MgSO₄), filtered and concentratedin vacuo. The crude residue was purified by silica gel chromatographyusing 0-50% EtOAc/hexanes gradient to afford 553 mg of desired product,58a, as an oil. LC/MS two peaks corresponding to two diastereomericproducts: 286.4 (M+H), RT=3.41 and 3.78.

Formation of (1R,3S)-1-allyl-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanoland (1R,3S)-1-allyl-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol(58b and 58c)

In a microwave tube was placed5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.57 g, 1.32 mmol) and(3S)-1-allyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol,58a, (0.32 g, 1.10 mmol) in acetonitrile (12 mL) and Na₂CO₃ (1.65 mL of2 M aqueous solution, 3.31 mmol). The mixture was deoxygenated withnitrogen for 15 min. To the mixture was added tetrakis triphenylphosphine palladium (0) (0.03 g, 0.02 mmol). The reaction was sealed andheated to 120° C. for 20 min. The mixture was diluted with brine,extracted twice with CH₂Cl₂.The combined organic phases were dried(MgSO₄), filtered and concentrated in vacuo. The resulting residue waspurified via silica gel chromatography using a 10-60% EtOAc/hexanesgradient to afford two diastereomers:

Diastereomer 1 (more polar spot—58c): LCMS RT=4.45 min, (M+H) =556.48

Diastereomer 2 (less polar spot -58b): LCMS RT=4.48 min (M+H)=556.48

Formation of 3-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol(58d)

To a solution of(3S)-1-allyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanol,58c, (0.30 g, 0.54 mmol) in 2-methyl-2-propanol (9.23 mL), THF (3.69 mL)and water (1.85 mL) was added pyridine (0.09 mL, 1.08 mmol) and osmiumtetroxide (0.27 mL of 2.5% w/v, 0.03 mmol) and 4-methylmorpholineN-oxide (0.07 mL, 0.65 mmol). The reaction mixture was heated to 80° C.for 20 hours. After cooling to room temperature, the mixture was dilutedinto aqueous saturated sodium bisulfite solution and extracted twicewith 20% isopropanol/CH₂Cl₂.The combined organic phases were washed withmore aqueous saturated sodium bisulfite solution, dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified viasilica gel chromatography using 5-10% MeOH/CH₂Cl₂ gradient to afford 175mg of the desired product as a racemic mixture, 58d.

¹H NMR (d6-DMSO) δ 8.77 (t, J=2.6 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.42(d, J=6.0 Hz, 1H), 8.25-8.23 (m, 1H), 8.07 (d, J=7.4 Hz, 2H), 7.74 (dd,J=7.6, 13.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 4.97 (d, J=12.8 Hz, 1H),4.76-4.72 (m, 1H), 4.54-4.51 (m, 1H), 4.31 (m, 1H), 3.83 (m, 1H), 2.36(s, 3H), 1.99-1.91 (m, 2H), 1.77-1.63 (m, 4H) and 1.57-1.46 (m, 4H) ppm;LCMS RT=4.31 (M+H) 590.5.

Formation of 3-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)—1-hydroxycyclohexyl)propane-1,2-diol(718)

To a solution of 3-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol,58d, (0.11 g, 0.18 mmol) in MeOH (5 mL) was added sodium methanolate (2mL of 25% w/v solution, 9.26 mmol) and the reaction mixture was stirredat room temperature. After 20 min, the reaction mixture was diluted withaqueous saturated NH₄C₁ solution and extracted twice with 20%IPA/CH₂Cl₂.The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo. Purification via silica gel chromatography using5-20% MeOH: CH₂Cl₂ gradient to afford 56 mg of a white solid.

¹H NMR (300 MHz, d6-DMSO) δ 12.29 (s, 1H), 8.71 (t, J=2.3 Hz, 1H), 8.27(d, J=2.4 Hz, 1H), 8.19 (dd, J=2.8, 4.5 Hz, 1H), 8.15 (t, J=3.7 Hz, 1H),7.52 (t, J=7.7 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.77 (dd, J=3.8, 10.5Hz, 1H), 4.54 (t, J=5.6 Hz, 1H), 4.32 (m, 1H), 3.86 (m, 1H), 2.00-1.97(m, 2H), 1.82-1.63 (m, 4H) and 1.59-1.45 (m, 4H) ppm; LCMS RT=3.71 (M+1)436.48.

Formation of dibenzyl (1S,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)—1-hydroxycyclohexylphosphonateand dibenzyl (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexylphosphonate(59a and 59b)

To a solution of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone,28a, (0.40 g, 0.78 mmol) in benzyloxyphosphonoyloxymethylbenzene (2.58mL, 11.67 mmol) was added triethylamine (0.22 mL, 1.56 mmol). Thereaction mixture was heated to 95° C. for 15 hours. The mixture wasdiluted with aqueous saturated NaHCO₃ solution, extracted with EtOAc,washed again with aqueous saturated NaHCO₃ solution. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo to white solid.The crude product was purified via silica gel chromatography using 0-10%MeOH/CH₂Cl₂ gradient to afford 518 mg of a mixture of diastereomers,which contains somebenzyloxyphosphonoylmethylbenzene. The mixture wasused without further purification in the next step. LCMS RT=4.6 (M+H)776.32.

Formation of dimethyl (1S,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexylphosphonateand dimethyl (1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexylphosphonate(741, 742)

To a solution of (1R,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-dibenzyloxyphosphoryl-cyclohexanoland (1S,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-dibenzyloxyin MeOH was added sodium methanolate and the reaction was stirred atroom temperature. After 15 min, the reaction mixture was diluted withaqueous saturated NH₄Cl solution and extracted twice with 20%IPA/CH₂Cl₂.The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo. The resulting residue was purified via silica gelchromatography using 0-5% MeOH:CH₂Cl₂ to elute impurity, 5%-10% to elutebottom two spots.

Diastereomer 1 [741]: ¹H NMR (300 MHz, DMSO) δ 12.32 (s, 1H), 8.70 (d,J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.8 Hz, 1H), 8.18 (d,J=3.9 Hz, 1H), 7.34 (d, J=7.1 Hz, 1H), 5.77 (d, J=2.9 Hz, 1H), 4.60 (s,1H), 3.73 (dd, J=10.1, 6.3 Hz, 6H), 2.30-2.15 (m, 1H), 2.04-1.86 (m,1H), 1.85-1.50 (m, 6H); LCMS RT=3.82 (M+1) 470.5.

Diastereomer 2 [742]: ¹H NMR (300 MHz, DMSO) δ 12.30 (s, 1H), 8.75 (d,J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 8.14 (d,J=4.0 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 5.38 (s, 1H), 4.55-4.36 (m, 1H),3.71 (d, J=3.1 Hz, 3H), 3.68 (d, J=3.2 Hz, 3H), 2.16-2.01 (m, 2H),2.00-1.72 (m, 3H), 1.71-1.41 (m, 2H), 1.39-1.18 (m, 1H); LCMS RT=3.70(M+1) 470.5.

Formation of Ethyl 2-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexypethanoate(60a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N₂. THF(8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL,4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at roomtemperature then heated to reflux. After cooling to room temperature, asolution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL)was added slowly to the zinc mixture. Then, a solution of(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b,(2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxedfor 2 hours then concentrated in vacuo. EtOAc and aqueous saturatedNaHCO₃ solution were added and the product was extracted with additionalEtOAc (3×), dried (Na₂SO₄) and concentrated in vacuo. Purification bysilica gel chromatography (Hexanes:EtOAc) separated 2 products. Thefirst peak was 60a (2.05 g, 6.18 mmol, 75%). LCMS+: 332.20 at 3.57 min(10-90% Me0—H, 3/5 grad/run, Formic Acid).

Formation of Ethyl 2-((1R, 3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexypethanoate(60c)

To a solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.31 g, 0.72 mmol) in acetonitrile (6.0 mL) was added ethyl 2-((lR,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexyl)ethanoate,60a, (0.20 g, 0.60 mmol) and degassed under N2. Na₂CO₃ (0.90 mL of 2 M,1.81 mmol) was added followed by Pd(PPh₃)₄ (0.10 g, 0.09 mmol). Thereaction was sealed and microwaved at 120° C. for 30 min. The materialwas concentrated under reduced pressure then diluted in EtOAc andaqueous saturated NaHCO₃, then extracted with additional EtOAc (3×),dried (Na₂SO₄) and concentrated in vacuo. The material was diluted inDCM and silica gel chromatography (Hexanes:EtOAc) gave 217 mg of product60c. LC MS+: 602.49 at 4.62 min (10-90% MeOH, 3/5 grad/run, FormicAcid).

Formation of 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoicacid (60d)

To a solution of ethyl 2-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate,60c, (0.14 g, 0.22 mmol) in THF (5.0 mL) was added LiOH (1.12 mL of 1 Maqueous solution, 1.12 mmol). The reaction was microwaved at 130° C. for30 min, neutralized with HCl (0.56 mL of 2 M, 1.12 mmol) andconcentrated under reduced pressure, diluted in toluene and concentrated(2×) to give 60d which was used without further purification. LC MS+:420.30 at 3.05 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-1-hydroxycyclohexyl)-N-methylethanamide(751)

To a solution of 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoicacid, 60d, (0.032 g, 0.076 mmol) in MeCN (1.6 mL) and DMF (1.6 mL) wasadded HATU (0.058 g, 0.152 mmol), Methanamine (0.154 mL of 2 M solution,0.305 mmol) and ^(i)Pr₂NEt (0.053 mL, 0.305 mmol). The reaction washeated to 60° C. overnight then concentrated in vacuo. The resultingresidue was purified by reverse phase HPLC (Water/HCl:MeOH). Purefractions were combined and concentrated in vacuo to give 29 mg of 751as the HCl salt.

Formation of Ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate(61b). (Step A):

Zinc dust (1.21 g, 18.47 mmol, 3 eq.) was heated with a heat gun underN₂. THF (6.0 mL) was added then a solution of chloro(trimethyl)silane(0.47 mL, 3.69 mmol) in THF (6.0 mL) was added and stirred for 15 min atroom temperature then heated to reflux and cooled. A solution of ethyl2-bromopropanoate (3.34 g, 18.47 mmol) and(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (61a)(1.50 g, 6.16 mmol) in THF (6.0 mL) was added to the zinc mixtureslowly. This mixture was refluxed for 2 hours then concentrated invacuo. EtOAc and aqueous saturated NaHCO₃ were added and the product wasextracted with EtOAc (3×), dried (Na₂SO₄) and concentrated in vacuo.Purification by silica gel chromatography (Hexanes:EtOAc) separated 2products. The first product eluted at 20-35% ethyl acetate and secondproduct eluted at 35-40%. The fractions of the 2^(nd) product wereconcentrated in vacuo to give 760 mg of 61b. LCMS+: 346.23 at 3.35 min(10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of Ethyl 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate(61c).

To a solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.21 g, 0.38 mmol) in acetonitrile (3.6 mL) was added ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexyl)propanoate(61b) (0.12 g, 0.35 mmol) and degassed under N₂. Na₂CO₃ (0.52 mL of 2 Maqueous solution, 1.041 mmol) was added followed by Pd(PPh₃)₄ (0.06 g,0.052 mmol). The reaction was sealed and heated in a microwave at 120°C. for 30 min. The material was concentrated under reduced pressure andthen diluted in EtOAc and aqueous saturated NaHCO₃, ten extracted withadditional EtOAc (3×). The combined organic phases were dried (Na₂SO₄)and concentrated in vacuo. The material was diluted in CH₂Cl₂ and silicagel chromatography (Hexanes:EtOAc) gave product 200 mg of 61c. LCMS+:600.35 at 4.22 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoicacid (61d).

To a solution of ethyl 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)propanoate(61c) (0.20 g, 0.33 mmol) in THF (3 mL) was added LiOH (3 mL of 1 Maqueous solution, 3.0 mmol). The reaction was allowed to stir over 2days at room temperature then neutralized with HC₁ (1.5 mL of 2M, 3.0mmol) and concentrated to dryness, diluted in toluene and concentratedagain (2×) to give 61d which was used without further purification.LCMS+: 418.32 at 2.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of (4R, 5S,7S)-7-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one(967).

To a solution of 2-[(1S,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-1-hydroxy-cyclohexyl]propanoicacid (61d) (0.095 g, 0.228 mmol) in toluene (5 mL) and triethylamine(0.048 mL, 0.341 mmol) was added (azido(phenoxy)phosphoryl)oxybenzene(0.059 mL, 0.273 mmol). The reaction was heated to 120° C. in a sealedtube overnight. The reaction was concentrated in vacuo and purified byreverse phase HPLC (Water/HCl:MeOH) to separate the diastereomers. Toremove a trace amount of leftover starting material, the first peak wasdiluted in MeOH (1 mL) and passed through a PL-HCO3 MP SPE cartridge toobtain the free base. This material was then salted (HCl in water) andconcentrated in vacuo to give 16 mg of 967 as the HCl salt.

Formation of (S)-ethyl2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate(62a).

To a solution of(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (29b)(2.00 g, 8.21 mmol) in toluene (40 mL) was added ethyl2-triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol). The reactionwas refluxed overnight then concentrated in vacuo and purified by silicagel chromatography (Hexanes:EtOAc). The desired product eluted at 15%ethyl acetate. Clean fractions were combined and concentrated to give2.57 g of 62a. LCMS+:314.18 at 3.75 min (10-90% MeOH, 3/5 grad/run,Formic Acid).

Formation of Ethyl2-((3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(nitromethyl)cyclohexypethanoate(62b)

To a solution of (S)-ethyl2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate,62a, (2.58 g, 8.22 mmol) in nitromethane (44.53 mL, 822.3 mmol) wasadded 1,1,3,3-tetramethylguanidine (1.55 mL, 12.33 mmol). The reactionwas refluxed overnight then concentrated in vacuo and purified by silicagel chromatography (Hexanes:EtOAc) then a second chromatography(CH₂Cl₂:20% MeOH in CH₂Cl₂). Fractions containing pure product werecombined and concentrated to give 1.8 g of 62b LCMS+:375.32 at 3.64 min(10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of(7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one(62c)

To a solution of ethyl2-((3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(nitromethyl)cyclohexyl)ethanoate,62b, (1.60 g, 4.27 mmol) in MeOH (20 mL) was added Raney Nickel (0.03 g,0.43 mmol). The reaction was shaken on a Parr apparatus at 40 psi of H₂overnight. The reaction was filtered, concentrated in vacuo and purifiedby silica gel chromatography (CH₂Cl₂:20% MeOH in CH₂Cl₂) to give 155 mgof 62c. LCMS+: 299.13 at 2.87 min (10-90% MeOH, 3/5 grad/run, FormicAcid).

Formation of(7S)-7-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one(62d).

To a solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.083 g, 0.195 mmol) in acetonitrile (1.6 mL) was added(7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one(62c) (0.053 g, 0.177 mmol) and degassed under N₂. Aqueous Na₂CO₃ (0.266mL of 2 M solution, 0.5320 mmol) was added followed by Pd(PPh₃)₄ (0.031g, 0.027 mmol). The reaction was sealed and heated in a microwave at120° C. for 30 min then concentrated in vacuo. The material was dilutedin CH₂Cl₂ and silica gel chromatography using a gradient ofHexanes:EtOAc then 20% MeOH in CH₂Cl₂.Pure fractions were combined andconcentrated to give 91 mg of 62d. LCMS+:569.26 at 4.20 min (10-90%MeOH, 3/5 grad/run, Formic Acid).

Formation of(7S)-7-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one(969).

To a solution of(7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one,62d, (0.091 g, 0.159 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25%w/v, 9.255 mmol). The reaction was stirred for 0.5 hours thenconcentrated in vacuo. The material was purified by reverse phase HPLC(Water/HC₁:MeOH) to give a mixture of diastereomers. The fractionscontaining pure product were combined and concentrated to give 50 mg ofthe HCl salt of 969.

Formation of ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate(63a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N₂. THF(8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL,4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at roomtemperature then heated to reflux and cooled. A solution of ethyl2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly tothe zinc mixture, then a solution of(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b,(2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxedfor 2 hours then concentrated in vacuo. EtOAc and aqueous saturatedNaHCO₃ solution were added and the product was extracted with additionalEtOAc (3×), dried (Na₂SO₄) and concentrated in vacuo. Purification bysilica gel chromatography (Hexanes:EtOAc) separated 2 products.Fractions containing the second (minor) peak were combined andconcentrated to give 470 mg of 63a. LCMS+:332.13 at 3.2 min (10-90%MeOH, 3/5 grad/run, Formic Acid).

Formation of (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-oxa-3-azaspiro[4.5]decan-2-one(63b).

To a solution of ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate,63a, (0.40 g, 1.20 mmol) in dry MeOH (6 mL) was added hydrazine (0.75mL, 23.4 mmol). The reaction was stirred overnight at room temperaturethen concentrated under a stream of N₂. The reaction was diluted withHCl (20 mL of a 1M solution, 20 mmol) until acidic and cooled to 0°-5°C. Then NaNO₂ (1.44 mL of a 1M solution, 1.44 mmol) was added slowly.1:1 Benzene:CHCl₃ (20 mL) was added and the mixture was stirred. Theorganic layer was separated and added slowly to refluxing benzene. Thiswas refluxed for 0.5 h then concentrated. Silica gel chromatography(CH₂Cl_(2:20)% MeOH in CH₂Cl₂) gave 92 mg of pure product 63b.LCMS+:301.15 at 2.76 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

Formation of (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one(63c)

A solution of (5S,9S)-9-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-oxa-3-azaspiro[4.5]decan-2-one,63b, (0.049 g, 0.163 mmol) in DMF (8.2 mL) was cooled to 0° C. NaH(0.010 mg, 0.244 mmol) was added followed by MeI (0.011 mL, 0.179 mmol).The reaction was allowed to warm to room temperature overnight. Thereaction was quenched with water and concentrated in vacuo. Aqueoussaturated NaHCO₃ solution was added and the product was extracted withEtOAc (3×), washed with brine, dried (Na₂SO₄) and concentrated in vacuo.The material was purified using silica gel chromatography (CH₂Cl₂:20%MeOH in CH₂Cl₂) to give 63b. LCMS+:315.19 at 2.83 min (10-90% MeOH, 3/5grad/run, Formic Acid).

Formation of(5S,7S)-7-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one(63d)

To a solution of5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,63c, (0.019 g, 0.060 mmol) and degassed under N₂. Na₂CO₃ (0.091 mL of 2M, 0.1810 mmol) was added followed by Pd(PPh₃)₄ (0.010 g, 0.009 mmol).The reaction was sealed and heated in a microwave at 120° C. for 30 min.The mixture was then concentrated in vacuo. The material was diluted inCH₂Cl₂ and silica gel chromatography (Hexanes:EtOAc then 20% MeOH inCH₂Cl₂) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5grad/run, Formic Acid).

(5S,7S)-7-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one(971)

To a solution of (5S,7S)-7-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,63d, (0.035 g, 0.060 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25%w/v, 9.255 mmol). The mixture was stirred for 30 min then concentratedin vacuo and purified by reverse phase HPLC (Water/HCl:MeOH). Purefractions were combined and concentrated in vacuo to afford product 971as the HCl salt.

Formation of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone(64a)

A microwave tube was placed5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(2.13 g, 4.93 mmol) and(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME(22.2 mL) and aqueous Na₂CO₃ (5.13 mL of 2 M solution, 10.26 mmol)solution. The mixture was deoxygenated with nitrogen for 20 min. To thereaction mixture was added tetrakis triphenylphosphane palladium (0.47g, 0.41 mmol). The reaction was sealed and heated to 120° C. for 30 min.The reaction was diluted with ethyl acetate (40 mL), filtered throughCelite. The filtrate was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. Purification via silica gel chromatography using10-80% EtOAc/hexanes gradient afforded(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone,64a.

Formation of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-trimethylsilyloxy-cyclohexanecarbonitrile(64b)

To a solution of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone,64a, (0.58 g, 1.13 mmol) in CH₂Cl₂ (20 mL) was added diiodozinc (0.36 g,1.13 mmol) and trimethylsilylformonitrile (0.30 mL, 2.26 mmol) at roomtemperature. The reaction was refluxed overnight. The mixture waspurified by silica gel chromatography to afford 600 mg of(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-trimethyl-silyloxy-cyclohexanecarbonitrile,64b.

Formation of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-hydroxy-cyclohexanecarboxylicacid (64c)

(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-trimethylsilyloxy-cyclohexanecarbonitrile,64b, (0.57 g, 0.93 mmol) was heated in HCl (20 mL of 12 M solution,240.0 mmol) at 80° C. in a sealed tube overnight. The solvent wasevaporated and the crude product was purified by preparatory HPLC toprovide 200 mg of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-hydroxy-cyclohexanecarboxylicacid, 64c.

¹H NMR (300 MHz, MeOD) δ 8.70 (d, J=2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d,J=2.2 Hz, 1H), 8.28 (d, J=5.5 Hz, 1H), 5.37-4.57 (m, 49H), 3.38-3.26 (m,26H), 2.42 (dd, J=13.3, 4.2 Hz, 2H), 2.15 (d, J=10.4 Hz, 1H), 2.07-1.87(m, 3H), 1.77 (dd, J=18.1, 8.6 Hz, 3H); LCMS: 406.35 (M+1).

Formation of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-1-hydroxy-cyclohexanecarboxamide(779)

(1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-hydroxy-cyclohexanecarboxylicacid, 64c, (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then^(i)Pr₂NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2 Msolution, 0.271 mmol) was added, followed by HATU (0.080 g, 0.210 mmol).The reaction was stirred at room temperature for another 2 hours. Thesolution was evaporated and the product was purified by Preparatory HPLCto afford 10 mg of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino] -N-ethyl-1-hydroxy-cyclohexanecarboxamide, 779.

¹H NMR (300 MHz, MeOD) δ 8.72 (d, J=2.2 Hz, 2H), 8.48 (s, 2H), 8.34 (dd,J=23.7, 3.9 Hz, 3H), 4.99 (d, J=5.4 Hz, 3H), 4.88 (s, 1H), 4.85-4.67 (m,32H), 3.44-2.95 (m, 4H), 2.29 (dd, J=13.5, 4.1 Hz, 3H), 2.11 (d, J=9.5Hz, 2H), 2.04-1.80 (m, 7H), 1.76 (s, 3H), 1.13 (t, J=7.2 Hz, 4H); LCMS:433.42 (M+1).

Formation of 3-amino-2-hydroxy-cyclohexanecarboxylic acid (65a)

2Hydroxy-3-nitro-benzoic acid (5.0 g, 27.3 mmol) was mixed with HCl (125mL of 0.5 M, 62.5 mmol) and dioxoplatinum (1.0 g, 4.4 mmol) in ahydrogenation bottle. The mixture was placed on a Parr shaker (50 psiH₂) for 24 hours. The catalyst was filtered and washed with hot H₂O. Thefiltrate was evaporated to provide3-amino-2-hydroxy-cyclohexanecarboxylic acid as a mixture ofstereoisomers which was utilized to the next step without furtherpurification.

Formation of3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylicacid (65b)

5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine,65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid(0.19 g, 0.97 mmol), ^(i)Pr₂NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL)solution was heated in microwave at 130° C. for 10 min. The solvent ofthe reaction mixture was removed under reduced pressure and the residuewas purified by preparatory HPLC to give 240 mg of3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylicacid, 65b, as a mixture of stereoisomers.

Formation of3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamide(65c)

3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylicacid, 65b, (0.100 g, 0.179 mmol) was dissolved in DMF (2 mL) and^(i)Pr₂NEt (0.124 mL, 0.714 mmol) and ethanamine hydrochloride (0.029 g,0.357 mmol) was added at room temperature. Then HATU (0.081 g, 0.214mmol) was added to the solution at room temperature. After 30 min, EtOAcwas added and the mixture was washed with 1 N HCl, aqueous saturatedNH₄Cl solution, and brine. The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was used in thenext step without further purification.

Formation of3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamide(815)

3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamide,65c, was treated with NaOMe in MeOH. The product was purified bypreparatory HPLC to provide3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-2-hydroxy-cyclohexanecarboxamideas a mixture of stereoisomers. LCMS: 433.35 (M+1).

Formation of Methyl-1-methylcyclohex-2-ene-1-carboxylate (66a)

To a cold (0° C.) solution of freshly distilledN-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) underargon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol).After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL,27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. andmethyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added.After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol)was added. The solution was then allowed to warm to 5° C. over 2 h. Anaqueous saturated solution of NH₄Cl was poured into the orange mixture.After dilution with hexanes and washing with brine, the organic layerwas dried over Na₂SO₄ and carefully evaporated to 3.3 g of generatemethyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used withoutfurther purification.

¹H NMR (300 MHz, CDCl₃) δ 5.77 (dt, J=10.1, 3.5 Hz, 1H), 5.66 (s, 1H),3.71-3.58 (m, 3H), 2.16 (ddd, J=12.9, 7.0, 3.4 Hz, 1H), 2.03-1.88 (m,2H), 1.72-1.53 (m, 2H), 1.49-1.37 (m, 1H), 1.32-1.14 (m, 3H).

Formation of racemic cis-methyl5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (66b)

Methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, (3.30 g, 21.40 mmol)was treated with 3-chloroperoxybenzoic acid (7.39 g, 42.80 mmol) inCH₂Cl₂ (75 mL) at room temperature for 2 hours. The solution was clearbut white precipitate was observed after 1 hour. The resulting whitesolid was filtered and washed with hexanes, and the filtration wasdiluted with EtOAc and washed with aqueous saturated NaHCO₃ solutionfollowed by brine. The organic phase was then dried overNa₂SO₄,concentrated in vacuo and the crude residue was purified bysilica gel chromatography (Hexanes/Ethyl acetate 100/0 to 10/1 gradient)to provide two products. The less polar spot is a colorless oil, whichis assigned by 1H NMR to be cis-methyl5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (1.2 g) and the secondfraction is a white solid, which istrans-methyl-5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (2.2 g).

Racemic cis-isomer (66b): ¹H NMR (300 MHz, CDCl₃) δ 3.67 (d, J=4.3 Hz,3H), 3.23-3.12 (m, 1H), 3.08 (d, J=3.8 Hz, 1H), 2.02-1.78 (m, 2H), 1.68(dtd, J=9.7, 6.8, 3.2 Hz, 1H), 1.49-1.27 (m, 2H), 1.25-1.15 (m, 3H),1.06 (ddd, J=9.1, 7.4, 3.2 Hz, 1H).

Formation of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate (66c)

Racemic cis-methyl-5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate,66b, (2.2 g, 12.93 mmol) was added to a flask containing MeOH (90 mL)and H₂O (10 mL) under nitrogen atmosphere. NH₄C₁ (1.38 g, 0.90 mL, 25.86mmol) and NaN₃ (2.52 g, 38.79 mmol) were then added to the reactionmixture. The mixture was heated to reflux for 16 hours. The solvent wasevaporated under reduced pressure and the oil was taken up in H₂O andextracted with EtOAc. The combined organic phases were washed with brineand dried over Na₂SO₄. The crude product was purified by silica gelchromatography to afford 900 mg of racemicmethyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate.

¹H NMR (300 MHz, CDCl₃) δ 3.74 (d, J=3.1 Hz, 3H), 3.64-3.43 (m, 2H),3.25-3.05 (m, 1H), 2.25-2.09 (m, 1H), 2.00 (ddd, J=9.7, 4.8, 2.9 Hz,1H), 1.73-1.50 (m, 1H), 1.40 (d, J=6.3 Hz, 3H), 1.32-1.03 (m, 3H).

Formation of racemicmethyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate (66d)

A solution of racemicmethyl-3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylate, 66c, (0.90 g,4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was stirredunder a hydrogen atmosphere (balloon) with the presence of palladium(0.50 g, 0.47 mmol) overnight at room temperature. The mixture wasfiltered through a celite bed and washed with MeOH. The combinedfiltrates were evaporated to providemethyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as a oil. Et₂Owas added and the resulted acetic acid salt was stirred for 0.5 hour andwas then filtered to give 1.0 g of racemicmethyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetic acidsalt as a white solid.

Formation of racemicMethyl-3-[(2-chloro-5-fluoro-pyrimidin-4-y0amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate(66e)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.43 g, 2.58 mmol)and racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylateacetic acid salt, 66d, (0.58 g, 2.35 mmol) in THF (10 mL) and MeOH (8mL) at room temperature was added ^(i)Pr₂NEt (1.23 mL, 7.04 mmol). Afterstirring the reaction overnight at room temperature, the solvent wasevaporated under reduced pressure and the crude residue was purified bysilica gel chromatography (Hexanes/EtOAc 100/0 to 0/100, Rf=0.7 inHexanes/EtOAc 2/1) to provide 650 mg of racemicmethyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate,66e, as a white solid. LCMS: 318.16 (M+1).

Formation of racemicMethyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate(66f)

To a solution of racemicmethyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate,66e, (0.65 g, 2.05 mmol) and5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na₂CO₃ (3.52 mL of2 M solution, 7.04 mmol). The solution was degassed with N₂ for 20minutes. Tetrakis triphenylphosphane palladium (0) (0.14 g, 0.12 mmol)was added and the mixture was refluxed overnight. LCMS showed goodconversion, but some starting materials remained. More degassed 2 NNa₂CO₃ was added followed by another portion of Tetrakistriphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction wasrefluxed for another 4 hours. The mixture was cooled to roomtemperature, extracted with EtOAc. The organic phase was washed by brineand dried over Na₂SO₄. After evaporation of solvent the crude mixturewas purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100)to provide 1.0 g of racemicmethyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate,66f. LCMS: 588.26 (M+1).

Formation of (1S, 2S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylicacid (928)

Racemicmethyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate,66f, (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL)and treated with aqueous LiOH (0.24 mL of 1 M solution, 0.24 mmol) andthe reaction was heated to reflux overnight. The reaction was cooled toroom temperature and the resulting material directly purified bypreparatory HPLC to afford 20 mg of racemic3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylicacid. The enantiomers of the racemic material were separated by chiralSFC purification to afford 6 mg of (1R, 2R,3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylicacid and 6 mg of (1S, 2S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylicacid. LCMS: 420.36 (M+1).

Formation (1R, 3S)-ethyl 3-aminocyclohexanecarboxylate (67b)

To a solution of (1R, 3S)-ethyl3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 18b, (14.0 g, 45.9mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol).The mixture was evacuated and then stirred under atmosphere of nitrogenat room temperature overnight. The reaction mixture was filtered througha pad of celite and the resulting filtrate concentrated in vacuo toprovide an oil that was used without further purification.

Formation (1R, 3S)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate (67c)

To a solution of (1R, 3S)-ethyl 3-aminocyclohexanecarboxylate, 67b, (5.1g, 24.1 mmol) and 2,4-dichloro-5,-fluoropyrimidine (6.0 g, 36.0 mmol) inTHF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). Themixture was heated to reflux overnight. The reaction was cooled to roomtemperature and concentrated in vacuo. The residue was diluted withwater and extracted twice with ethyl acetate. The combined organicphases were dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0-40% EtOAc/hexanesgradient) to provide 6.7 g of (1R, 3S)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as awhite solid: LCMS RT=3.1 (M+H) 302.2.

Formation (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid(67d)

To a solution of (1R, 3S)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate, 67c,(20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOHhydrate (8.3 g, 198.8 mmol) in 100 ml water. The reaction mixture wasstirred at 50° C. overnight, To the reaction mixture was added HCl (16.6mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washedwith brine and dried over MgSO₄ and the solvent was removed underreduced pressure to afford 17.5 g of product that was used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=2.7 Hz, 2H),5.24 (d, J=7.3 Hz, 2H), 4.19-4.03 (m, 3H), 3.84-3.68 (m, 3H), 2.59 (ddd,J=11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, J=12.4 Hz, 2H), 2.08 (d, J=9.6 Hz,6H), 1.99-1.76 (m, 5H), 1.63-1.34 (m, 6H), 1.32-1.15 (m, 4H).

Formation N-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)-pyrrolidine-1-carboxamide(67e)

A solution of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylic acid,67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL,45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) wasdegassed under nitrogen for 15 minutes. The reaction mixture was heatedat 85° C. for 30 minutes until LC/MS indicated complete consumption ofcarboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5mL, 90.0 mmol) and the reaction was heated at 85° C. for an additional15 min. The mixture was diluted into brine and extracted with EtOAc. Theorganic phase was separated, dried over MgSO₄. The product was isolated(6.25 g) by filtration after partial removal of solvent in vacuo: ¹H NMR(300 MHz, CDCl₃) δ 7.87 (d, J=2.8 Hz, 2H), 5.04 (d, J=8.1 Hz, 2H), 4.09(ddd, J=26.9, 13.4, 5.6 Hz, 4H), 3.91-3.71 (m, 2H), 3.32 (t, J=6.5 Hz,7H), 2.45 (d, J=11.5 Hz, 2H), 2.08 (dd, J=22.1, 12.0 Hz, 4H), 1.96-1.82(m, 9H), 1.54 (dd, J=18.6, 8.5 Hz, 2H), 1.22-1.01 (m, 6H).

Formation N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide(67f)

A solution of N-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)-pyrrolidine-1-carboxamide,67e, (6.8 g, 20.0 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,44a, (12.5 g, 30.0 mmol) and K₃PO₄ (17.0 g, 80.0 mmol) in 2-methyl THF(180 mL) and water (20 mL) was degassed under nitrogen for 30 min. Tothe mixture was addeddicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) (1.1g, 2.4 mmol) and Pd₂(dba)₃ (0.5 g, 0.5 mmol). The reaction mixture washeated in a pressure bottle at 125° C. for 2.5 hr. The reaction mixturewas filtered through celite, the solvent was removed under reducedpressure. The resulting residue was purified by silica gelchromatography (8%MeOH/CH₂Cl₂) to afford 11.5 g of the desired product:¹H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.49 (dd, J=9.0, 2.8 Hz, 1H),8.32 (d, J=2.1 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 8.07 (d, J=3.2 Hz, 1H),7.30 (d, J=8.5 Hz, 2H), 4.98 (d, J=6.3 Hz, 1H), 4.37-4.16 (m, 1H), 4.08(d, J=7.3 Hz, 1H), 3.99-3.80 (m, 1H), 3.33 (t, J=6.5 Hz, 4H), 2.52 (d,J=11.6 Hz, 1H), 2.39 (s, 3H), 2.29 (d, J=11.3 Hz, 1H), 2.12 (d, J=11.1Hz, 1H), 1.99-1.81 (m, 5H), 1.70-1.55 (m, 1H), 1.22-1.08 (m, 2H).

Formation N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide(895)

A solution of N-((lR,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide,67f, (11.5 g, 19.3 mmol) in THF (150 mL) was added sodium methoxide(4.173 g, 19.31 mmol). After stirring the reaction mixture for 2minutes, the mixture was poured into an aqueous saturated solution ofNaHCO₃. The organic phase was washed with brine, dried over MgSO₄ andthe solvent was removed under reduced pressure. The resulting residuewas purified by silica gel chromatography (10%MeOH/CH₂Cl₂) to afford6.5g of the desired product. The product was converted to an HCl salt bydissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution atroom temperature. The solution was stirred at for lhour and the HCl saltprecipitated out and filtered to provide 7.05g of the HCl salt: ¹H NMR(300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, J=3.0 Hz, 2H), 8.49 (d, J=5.6Hz, 2H), 8.41 (dd, J=2.6, 1.4 Hz, 2H), 8.31 (d, J=9.5 Hz, 2H), 5.92 (s,3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J=6.6 Hz, 7H), 2.07 (dt,J=22.7, 11.5 Hz, 4H), 1.87 (t, J=12.6 Hz, 4H), 1.77 (dd, J=8.0, 5.3 Hz,7H), 1.65-1.13 (m, 8H).

Formation of 5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ol (68a)

To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-ol (1.2 g, 7.9mmol) in 80 mL DMF at 0° C. was added toluenesulfonyl chloride (1.8 g,9.5 mmol) followed by NaH (0.8 g, 19.7 mmol, 60% w/w). The reaction wasslowly warmed to 45° C. after 3 hours and stirred for an additional 3hours. The mixture was then concentrated in vacuo. The crude oil wasdissolved in 100 mL EtOAc and washed with water (2×50 mL) and brine. Theorganic phase was dried over sodium sulfate and concentrated in vacuo.The resulting residue was purified via silica gel chromatography (10%EtOAc/Hexanes) to afford 1.5 g of the desired product.

Formation of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (68b)

To a solution of 5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ol, 68a,(0.70 g, 2.29 mmol) in DMF (25 mL) was added methyliodide (0.14 mL, 2.29mmol) and K₂CO₃ (0.32 g, 2.29 mmol). The reaction mixture was stirredfor 3 hours at ambient temperature. The reaction was diluted withdeionized water and EtOAc. The organic phase was washed with brine,dried over sodium sulfate and concentrated in vacuo to afford 720 mg ofthe desired product that was used in next step without furtherpurification.

Formation of5-fluoro-4-methoxy-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (68c)

To a cold (0° C.) solution of5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68b, (0.79 g, 2.45mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). Thereaction mixture was stirred at 0° C. for 3 hours and then slowly warmedto ambient temperature. The mixture was diluted with deionized water andquenched with aqueous sodium bicarbonate. The aqueous phase wasextracted with methylene chloride and dried over sodium sulfate. Theresulting solid was purified via silica gel chromatography (15-30%EtOAc/Hexanes) to give 170 mg of the desired product.

Formation of5-fluoro-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(68d)

To a solution of5-fluoro-4-methoxy-3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 68c, (0.17g, 0.43 mmol) in 2-Me-THF (9 mL) in a microwave vial was addedbis(pinacol)diborane (0.16 g, 0.64 mmol), followed by potassium acetate(0.23 g, 1.06 mmol) and palladium (II) dichlorobis(tricyclohexylphosphane) (0.02 g, 0.02 mmol). Reaction vial wassealed and irradiated with microwaves at 125° C. for 90 minutes. Themixture was filtered and purified via silica gel chromatography (10-30%EtOAc/Hexanes) to afford 100 mg of the desired product.

Formation of (R)-3-fluoro-N-((1R,3S)-3-((5-fluoro-2-(5-fluoro-4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide(1104)

To a solution of5-fluoro-4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,68d, (0.100 g, 0.220 mmol) in 2-Me-THF (2 mL) was added (R)-N-((1R,3S)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)-3-fluoropyrrolidine-1-carboxamide(0.060 g, 0.170 mmol). Potassium phosphate (0.130 g, 0.600 mmol) anddeionized water (0.5 mL) were then added and solution was degassed undera flow of nitrogen for 10 minutes.2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (0.006 g,0.012 mmol) and tris(dibenzylideneacetone)-dipalladium (O) (0.023 mg,0.026 mmol) were then added and solution was again degassed under flowof nitrogen for 5 minutes. Vial was sealed and heated to 80° C. for 3hours. Solution cooled to ambient temperature and was filtered andconcentrated in vacuo. The crude oil was redissolved in anhydrous THF (5mL) and a solution of 2N LiOH (2 mL) was added. The reaction mixture washeated to 80° C. for 2 hours. Solution was cooled to ambient temperatureand concentrated in vacuo. Purification by preparative HPLC afforded 6mg of the desired product.

Formation of 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexyl)-ethanenitrile(69a)

A suspension of2-chloro-5-fluoro-N-[(3S)-1-oxaspiro[2.5]octan-7-yl]pyrimidin-4-amine,49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithiumperchlorate (0.25 g, 2.33 mmol) in CH₃CN was heated at 100° C. in apressure tube for 3 h. The mixture was diluted into EtOAc and theorganic phase was washed with aqueous saturated NaHCO₃ solution, driedwith MgSO₄, filtered and the solvent was removed under reduced pressure.The resulting residue was purified by silica gel chromatography(EtOAc/hexanes) afforded the desired product: ¹H NMR (300.0 MHz, CDCl₃)δ 7.78 (d, J=2.7 Hz, 1H), 4.85 (d, J=6.6 Hz, 1H), 4.28 (qn, J=4.0 Hz,1H), 2.45 (s, 2H), 2.16 (d, J=13.0 Hz, 1H), 2.05 (d, J=11.7 Hz, 1H),1.80-1.71 (m, 3H), 1.46-1.28 (m, 2H) and 1.17-1.06 (m, 1H) ppm; LCMSRT=2.15 (M+H) 285.34.

Formation of 2-((1S, 3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexypethanenitrile(69b)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,44a, (0.23 g, 0.55 mmol), 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)-ethanenitrile,69a, (0.14 g, 0.50 mmol) and Na₂CO₃ (0.75 mL of 2M solution, 1.50 mmol)in dimethoxyethane (15 mL) was degassed with nitrogen for 30 min. To thereaction mixture was added palladium; triphenylphosphane (0.03 g, 0.03mmol) and continued to degas the solution for 15 min. The reactionmixture was heated at 120° C. in a pressure tube for 45 min. Thereaction mixture was filtered through celite and the filtrate wasremoved under reduced pressure. The resulting residue was purified bysilica gel chromatography (40%EtOAc/Hexanes) to afford 150 mg of desiredproduct: LCMS RT=3.55 (M+H) 539.42.

2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexypethanenitrile(979)

To a solution of 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanenitrile,69b,(0.14 g, 0.26 mmol) in methanol (10 mL) was added sodium methoxide(0.06 g, 0.26 mmol). After stirring at room temperature for 2 minutes,the reaction mixture was diluted into EtOAc and brine. The separatedorganic phase was dried over MgSO₄, filtered, and concentrated in vacuo.The resulting residue was purified by silica gel chromatography(10%MeOH/CH₂Cl₂) to afford 46 mg of desired product: ¹H NMR (300.0 MHz,MeOD) δ 8.65 (dd, J=2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J=2.0, 2.5Hz, 1H), 7.98 (d, J=4.1 Hz, 1H), 4.66 (dd, J=8.0, 15.8 Hz, 1H), 2.64 (s,2H), 2.20 (d, J=12.6 Hz, 2H), 2.01 (dd, J=3.4, 9.8 Hz, 2H), 1.84-1.75(m, 1H), 1.63-1.47 (m, 2H), 1.33 (dd, J=3.6, 12.4 Hz, 1H) ppm; LCMSRT=2.31 (M+H) 385.45.

Formation of tert-butyl (tert-butoxycarbonylamino)((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylamino)methylenecarbamate(70b)

To a solution of (1S,3R)-N1-(2-chloro-5-fluoro-pyrimidin-4-yl)cyclohexane-1,3-diamine, 70a,(0.122 g, 0.500 mmol) in CH₂Cl₂ (10 mL) was added tert-butylN-(N-tert-butoxycarbonylC-pyrazol-1-yl-carbonimidoyl)carbamate (0.155 g,0.500 mmol). The reaction mixture was stirred at room temperature for 2days. The reaction mixture was concentrated in vacuo and used withoutfurther purification: ¹H NMR (300 MHz, CDCl3) δ 11.51 (s, 3H), 8.29 (d,J=8.3 Hz, 3H), 7.88 (d, J=2.8 Hz, 3H), 5.01 (d, J=7.4 Hz, 3H), 4.28-4.18(m, 4H), 2.48 (d, J=11.7 Hz, 3H), 2.12 (d, J=9.4 Hz, 3H), 1.87 (dd,J=10.3, 3.5 Hz, 3H), 1.52 (s, 24H), 1.50 (s, 25H), 1.24-1.10 (m, 8H);LCMS RT=3.97 (M+H) 487.12.

Formation of tent-butyl N-[N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamimidoyl]-carbamate(70c)

Degassed a solution of (Z)-tert-butyl (tert-butoxycarbonylamino) ((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylamino)methylenecarbamate, 70b, (0.200 g, 0.411 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.205 g, 0.493 mmol)and Na₂CO₃ (0.616 mL of 2M solution, 1.232 mmol) in dimethoxyethane (15mL) for 30 min. To the mixture was added palladium triphenylphosphane(0.023 g, 0.021 mmol) and the reaction mixture was heated in a pressuretube at 120° C. for 45 min. The reaction mixture was filtered through apad of celite and the filtrate concentrated in vacuo. Attemptedpurification of the resulting residue by silica gel chromatography (10%MeOH/CH₂Cl₂) yielded a mixture containing mostly desired product thatwas used without further purification: LCMS RT=2.30 (M+H) 641.02.

Formation of 1-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)guanidine(1143)

To a solution of tert-butyl N-[N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamimidoyl]carbamate,70c, (0.100 g, 0.156 mmol) in THF (20 mL) was added sodium methoxide(0.033 g, 0.156 mmol) at room temperature. After 1 minute, the reactionmixture was diluted into EtOAc and aqueous saturated NaHCO₃ solution.The organic phase was dried over MgSO₄, filtered and the solvent wasremoved under reduced pressure. The resulting residue was purified bysilica gel chromatography to afford 95mg of the desired product. To 10ml MeOH solution of the product was added hydrochloride/IPA (0.031 mL of5 M solution, 0.156 mmol). The reaction mixture was stirred at roomtemperature for 1 hour after which the solvent was removed under reducedpressure to afford the product, as hydrochloride salt: ¹H NMR (300 MHz,MeOD) δ 8.63 (s, 1H), 8.40 (dd, J=9.1, 2.7 Hz, 1H), 8.36 (s, 1H), 8.32(d, J=5.5 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H), 3.78-3.53 (m, 1H), 2.41 (d,J=11.7 Hz, 1H), 2.28 (d, J=12.0 Hz, 1H), 2.18-1.98 (m, 2H), 1.69 (dd,J=23.6, 11.8 Hz, 2H), 1.56-1.28 (m, 2H); LCMS RT=1.45 (M+H) 387.06.

Formation of methyl 2-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexylamino)oxazole-4-carboxylate(71a)

To a solution of (1S,3R)-N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine,44e, (0.089 g, 0.178 mmol) in DMF (1.5 mL) was added methyl2-chlorooxazole-4-carboxylate (0.031 g, 0.195 mmol), followed by DBU(0.029 mL, 0.195 mmol). The reaction mixture was allowed to stir at roomtemperature overnight. The reaction was warmed to 75° C. and allowed tostir for 3 hours. Added an additional 16 mg of the chlorooxazole esterand the reaction was heated at 75° C. overnight. The mixture was dilutedinto water and EtOAc. The layers were separated and the organic phasewas washed with brine, dried over MgSO₄, filtered and evaporated todryness. The crude residue was purified by silica gel chromatography(0-20%MeOH/CH₂Cl₂) to afford 28 mg of desired product: LCMS RT=3.73(M+1) 624.12.

Formation of 2-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexylamino)oxazole-4-carboxylicacid (1144)

To a solution of methyl 2-[[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]-amino]oxazole-4-carboxylate,71a, (0.028 g, 0.045 mmol) in THF (1 mL) was added LiOH (1 mL of 1 Msolution, 1.000 mmol) and the reaction mixture was warmed to 130° C. viamicrowave irradiation. After heating and stirring for 20 minutes, themixture was cooled to room temperature. All volatiles were removed undera stream of nitrogen and heat. The crude residue was suspended in MeOHand a few drops of trifluoroacetic acid were added to protonate molecule(solution occurs). The mixture was filtered and purified by reversephase HPLC (5-95% CH₃CN/H₂O) to afford 5 mg of the desired product as aTFA salt: ¹H NMR (300 MHz, MeOD) δ 8.83 (s, 1H), 8.67-8.09 (m, 4H), 2.67(s, 3H), 2.18 (m, 5H), 1.34 (d, J=29.6 Hz, 3H); LCMS RT=1.78 (M+1)456.07.

Formation of 6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one(72a)

To a solution of bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (25.0 mL,204.3 mmol) in NaHCO₃ (51.5 g, 612.9 mmol) in water was added bromine(32.7 g, 204.3 mmol) dropwise at 0° C. The solution was stirred for 1hour and extracted with ether, and the organic phase was washedsuccessively with 1 N Na₂S₂SO₃ solution and brine, and the organic phasewas then dried (Na₂SO₄), filtered and concentrated in vacuo to afford 30g of crude product that was used without further purification.

Formation of 6—oxonorbornane-2-carboxylic acid (72b)

6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one, 72a, (28.0 g,129.0 mmol) was treated with NaOH (258.0 mL of 2 M solution, 516.0 mmol)in H₂O (350 mL) for 2 hour at room temperature. The reaction mixture wasacidified with conc. HCl, extracted with Et₂O. The organic phase wasdried (Na₂SO₄), filtered and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-20% MeOH/CH₂Cl₂gradient) to provide 16 g of 6-oxonorbornane-2-carboxylic acid.

Formation of Endo methyl 6-oxonorbornane-2-carboxylate (72c)

A solution of 6-oxonorbornane-2-carboxylic acid, 72b, (16.0 g, 103.8mmol) in methanol (350.0 mL) was treated with TMSCl (42.04 g, 49.11 mL,387.0 mmol). The reaction mixture was stirred at room temperatureovernight. Solvent was evaporated under reduced pressure and the crudeproduct was purified by silica gel chromatography (10% EtOAc/hexanes) toprovide 12 g of Endo methyl 6-oxonorbornane-2-carboxylate.

Formation of Exo methyl 6-oxonorbornane-2-carboxylate (72d)

Endo methyl 6-oxonorbornane-2-carboxylate, 72c, (3.5 g, 20.8 mmol) washeated in a sealed tube in sodium methoxide (2.1 mL of 2 M solution inmethanol, 4.2 mmol) at 150° C. for 17 hours. The solvent was evaporatedand the crude product was purified by silica gel chromatography (0-16%EtOAc/hexanes gradient) to afford 3.3 g of starting endo methyl 6-oxonorbornane-2-carboxylate as the first fraction (PMA staining) and 4.0g of the desired exo product as the second spot. The recovered startingmaterial was treated with the same conditions again to generate another1.0 g desired exo-product.

Formation of methyl 6-hydroxynorbornane-2-carboxylate (72e)

To a solution of exo methyl 6-oxonorbornane-2-carboxylate, 72d, (4.7 g,27.9 mmol) in MeOH (50 mL) was added sodium borohydride (1.6 g, 41.9mmol) in five portions at 0° C. TLC showed completed conversion after 2hours. Aqueous saturated NH₄Cl solution was added to quench thereaction. The MeOH was evaporated under reduced pressure and then theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The resulting residue was purified by silica gel chromatography(0-100% EtOAc/hexanes, Rf=0.5 in 50% EtOAc/hexanes) to afford 3.96 g ofthe desired product: ¹H NMR (300 MHz, CDCl3) δ 4.23-4.06 (m, 1H), 3.56(s, 3H), 3.37 (s, 1H), 3.03 (dd, J=8.9, 5.5 Hz, 1H), 2.41 (d, J=3.9 Hz,1H), 2.13 (s, 1H), 1.93-1.69 (m, 2H), 1.63-1.42 (m, 1H), 1.34 (ddt,J=10.3, 3.2, 1.6 Hz, 1H), 1.20 (dd, J=10.4, 0.7 Hz, 1H), 0.77 (dt,J=12.6, 3.4 Hz, 1H).

Formation of methyl6-(N-(tert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicycle12.2.11heptane-2-carboxylate (72f)

To a cold (0° C.) solution of methyl 6-hydroxynorbornane-2-carboxylate,72e, (3.2 g, 18.8 mmol) in THF (150 mL) was added ethyl2-(tert-butoxycarbonylamino)-2-oxo-acetate (4.9 g, 22.6 mmol) andtriphenylphosphine (5.9 g, 22.6 mmol) followed by dropwise addition ofdiisopropyl azodicarboxylate (4.5 g, 22.6 mmol). The reaction was thenheated to 85° C. and maintained at that temperature for 2 days. Thesolvent was evaporated under reduced pressure and the crude product waspurified by silica gel chromatography (0-100% EtOAc/hexanes gradient) toprovide 6 g of methyl6-(N-(tert-butoxycarbony0-2-ethoxy-2-oxoacetamido)bicyclo[2.2.1]heptane-2-carboxylate:LCMS 392.34 (M+Nal; 1H NMR (300 MHz, CDCl3) δ 4.26 (q, J=7.2 Hz, 2H),4.08 (dt, J=14.3, 7.2 Hz, 1H), 3.62 (d, J=2.1 Hz, 3H), 2.72 (s, 1H),2.42-2.26 (m, 2H), 2.08-1.80 (m, 2H), 1.80-1.51 (m, 3H), 1.45 (s, 9H),1.38-1.25 (m, 3H).

Formation of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid(72g)

To a solution of methyl6-[tert-butoxycarbonyl-(2-ethoxy-2-oxo-acetyl)amino]norbornane-2-carboxylate,72f, (0.80 g, 2.17 mmol) in methanol (20 mL) was added NaOH (4.33 mL of2N solution, 8.66 mmol) at room temperature. The reaction mixture wasstirred overnight. The mixture was diluted into 0.5 N HCl in ice, andextracted twice with EtOAc. The combined organic phases were dried(Na₂SO₄), filtered and concentrated in vacuo to afford 600 mg of desiredproduct that was used without further purification.

Formation of 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid (72h)

A solution of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid,72g , in dichloromethane (5 mL) was treated with trifluoroacetic acid (5mL) for 1 hour at room temperature. The solvent was evaporated underreduced pressure and the resulting product was dissolved in 2 mL TFA andadded to a stirring 1N HCl in Et₂O solution. After stirring the mixturefor 0.5 hour, the resulting precipitate was filtered and washed with dryEt₂O to give 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid.

Formation of6-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylicacid (72j)

To a solution of5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.187 g, 0.417 mmol) and6—aminobicyclo-[2.2.1]heptane-2-carboxylic acid, 72 h, (0.080 g, 0.417mmol) in THF (3 mL) was added diisopropylethylamine (0.291 mL, 1.670mmol). The reaction mixture was heated at 80° C. overnight. Aqueous LiOH(3 mL of 2M solution, 6.000 mmol) was added and the mixture was heatedfor another 7 hours. The mixture was diluted with MeOH, neutralized withtrifluoroacetic acid, filtered and the resulting filrate was purified bypreparatory HPLC chromatography to afford 50 mg of desired product.

Formation ofN-[6-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]norbornan-2-yl]pyrrolidine-1-carboxamide(1045)

To a solution of6-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]norbornane-2-carboxylicacid, 72j, (0.030 g, 0.078 mmol) in THF (0.375 mL) was addedtriethylamine (0.032 mL, 0.234 mmol) and(azido(phenoxy)phosphoryl)oxybenzene (0.018 mL, 0.085 mmol). Thereaction mixture was heated to 95° C. for 2.5 hours, cooled down to 5°C., and treated with pyrrolidine (0.010 mL, 0.117 mmol). The reactionwas stirred for 3 days at room temperature. The reaction mixture wasinjected directly into a preparatory HPLC system for purification toprovide the product as a racemic mixture. The single enantiomers wereobtained by separation using SFC chiral purification to afford 5.7 mg ofthe desired product as well as 1.4 mg of the enantiomer.

Formation of (1R, 2R,3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol(73b)

Aminodiol, 73a, was synthesized by following the literature procedure(JOC 2009, 74, 6735). Aminodiol (0.040 mg), diisopropylethylamine (0.054mL, 0.310 mmol) and5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(0.139 g, 0.310 mmol) in THF was refluxed overnight. The solution wasconcentrated in vacuo and purified by silica gel chromatography (0-100%EtOAc/CH₂Cl₂) to give 43 mg of desired product as a white solid: ¹H NMR(300 MHz, CDCl3) δ 8.40 (q, J=2.8 Hz, 2H), 8.22 (d, J=1.8 Hz, 1H),8.08-7.94 (m, 3H), 7.20 (d, J=10.1 Hz, 3H), 5.26 (d, J=4.9 Hz, 1H),4.21-3.99 (m, 1H), 3.84 (s, 1H), 3.75-3.57 (m, 1H), 3.43 (t, J=8.7 Hz,1H), 2.73 (s, 1H), 2.30 (s, 3H), 2.11-1.85 (m, 2H), 1.84-1.36 (m, 8H),1.18 (s, 2H), 0.79 (dd, J=15.0, 6.8 Hz, 2H). LCMS (+H): M/Z=530.29

Formation of (1R, 2R,3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol(984)

LiOH (0.5 mL of 1N solution, 0.5 mmoL) was added to (1R, 2R,3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-1,2-diol,73a, in THF (3 mL). The reaction mixture was heated in microwave at 130°C. for 40 minutes. HCl (0.5 mL of 1.25 N solution in MeOH) and MeOH wasadded to the mixture.

The solution was purified by preparative HPLC (MeCN/H₂O 10-70%) to givedesired product as TFA salt. Neutralization and re-acidification withhydrogen chloride (1N in MeOH) afforded the desired product (28 mg) as awhite solid (HCl salt): ¹H NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 8.48 (d,J=2.8 Hz, 1H), 8.34 (s, 1H), 8.28 (d, J=5.6 Hz, 1H), 4.62-4.35 (m, 1H),3.65 (m, 2H), 2.11-1.43 (m, 8H); ¹⁹F NMR (282 MHz, MeOD) δ-137.38-137.51(m, 1H), −156.06 (d, J=5.6 Hz, 1H); LCMS (+H): M/Z=376.28.

Formation of benzyl ((1S, 3R)-3-(pyrazin-2-ylamino)cyclohexyl)carbamate(74a)

A suspension of CuI (0.006 g, 0.030 mmol), benzyl N-[(1S,3R)-3-aminocyclo-hexyl]carbamate, 18e, (0.075 g, 0.302 mmol) and cesiumcarbonate (0.197 g, 0.604 mmol) in DMF was evacuated and refilled withnitrogen multiple times. 2-iodopyrazine (0.036 mL, 0.362 mmol) and2-(2-methylpropanoyl)cyclohexanone (0.020 mL g, 0.121 mmol) were thenadded and the reaction was stirred at room temperature overnight. Thereaction was diluted into ethyl acetate and aqueous saturated sodiumbicarbonate. The organic phase was separated, dried (MgSO₄), filteredand concentrated in vacuo. The crude residue was purified by silica gelchromatography (0-10% MeOH/CH₂Cl₂) to afford 40 mg of the desiredproduct as yellow solid.

Formation of (1R, 3S)-N1-(pyrazin-2-yl)cyclohexane-1,3-diamine (74b)

To a solution of benzyl N-[(1S,3R)-3-(pyrazin-2-ylamino)cyclohexyl]carbamate, 74a, (0.040 g, 0.123mmol) in methanol (10 mL) was added 10% Pd/C (0.043 g, 0.040 mmol) andthe resulting suspension was stirred under an atmosphere of hydrogen forthree hours until LCMS indicated completion of the reaction. Thesolution was filtered through a bed of celite and concentrated in vacuoto give a yellow solid, which was used without further purification.

Formation of (1S,3R)-N1-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)-N3-(pyrazin-2-yl)cyclohexane-1,3-diamine(74c)

A solution of (1R, 3S)-N1-pyrazin-2-ylcyclohexane-1,3-diamine 74b,diisopropylethylamine (0.30 mmol) and5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine(0.06 g, 0.13 mmol) in THF (3 mL) was refluxed overnight. The mixturewas then concentrated in vacuo and the resulting residue was purified bysilica gel chromatography (0-20% MeOH/CH₂Cl₂ gradient) to afford 39 mgof desired product: ¹H NMR (300 MHz, CDCl3) δ 8.91-8.72 (m, 1H), 8.50(d, J=11.8 Hz, 1H), 8.38 (t, J=7.5 Hz, 1H), 8.06 (dd, J=14.8, 5.9 Hz,3H), 7.88 (d, J=1.4 Hz, 1H), 7.82 (s, 1H), 7.62 (t, J=6.8 Hz, 1H), 7.33(dd, J=16.6, 7.1 Hz, 3H), 5.91 (s, 1H), 4.27 (s, 1H), 3.98 (t, J=11.3Hz, 1H), 2.59 (d, J=12.0 Hz, 1H), 2.39 (s, 3H), 2.34-2.09 (m, 2H), 1.99(d, J=14.0 Hz, 1H), 1.72 (dd, J=26.6, 13.1 Hz, 1H), 1.48-1.08 (m, 4H).LCMS (+H): M/Z =593.25

Formation of (1S,3R)-N1-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)-N3-(pyrazin-2-yl)cyclohexane-1,3-diamine(985)

LiOH (0.3 mL of 1N solution, 0.3 mmoL) was added to a solution of (1S,3R)-N1-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)-N3-(pyrazin-2-yl)cyclohexane-1,3-diamine,74c, (35 mg) in THF (3 mL) and the reaction was heated in the microwaveat 130° C. for 40 minutes. A solution of HCl (0.5 mL of a 1.25N in MeOH)was added and the resulting solution was purified by Gilson HPLC(MeCN/H₂O 10-70% in 8 mins) to give pure TFA salt product.Neutralization and re-acidification with hydrogen chloride (1.25N inMeOH) afforded 23 mg of the HCl salt of the desired product as a lightyellow solid: ¹H NMR (300 MHz, MeOD) δ 8.76 (d, J=2.4 Hz, 1H), 8.63 (s,1H), 8.41 (d, J=2.3 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.16 (s, 1H), 7.96(s, 1H), 7.76 (s, 1H), 4.51 (m, J=11.8 Hz, 1H), 4.16-3.92 (m, 1H),2.35-2.14 (m, 2H), 2.09 (m, J=13.8 Hz, 1H), 1.63 (d, J=11.8 Hz, 4H); ¹⁹FNMR (282 MHz, MeOD) δ-155.25 (s, 1H); LCMS (+H): M/Z =439.24.

Formation of (1R,3S)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexanol (75a)

Mixed (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone,18e, (1.05 g, 4.31 mmol) in MeOH (20 mL) and dichloromethane (10 mL) andcooled to −78° C. using an external dry-ice/acetone bath and monitoredwith an internal thermometer. After 30 minutes, NaBH₄ (0.16 g, 4.31mmol) was added in one portion and continued to stir. (slight exotherm)and then cooled back down to -78° C. The reaction was monitored by HPLCfor consumption of starting material as it was allowed to warm to roomtemperature overnight. The reaction was diluted with brine and EtOAc.The organic phase was dried (MgSO₄), filtered and concentrated in vacuo.The resulting residue was purified by silica gel chromatography toafford 1.0 g of a colorless foamy solid: LCMS method m201:10-90CH₃CN/H2, formic acid modifier, 5 minutes, (C₁₈); RT=2.08min,MH+=246.21.

Formation of (1R,3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexanol(75b)

K₃PO₄ (2.59 g, 12.21 mmol) in water (6 mL) and 2-Me-THF (20 mL) waspurged with a flow of nitrogen for 30 min. Added(1R,3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 75a,(1.00 g, 4.07 mmol) and5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,44a, (2.03 g, 4.88 mmol) and then purged with nitrogen for another 15min. The reaction was then heated to 70° C. and then charged withTris(dibenzylideneacetone)dipalladium (0.07 g, 0.08 mmol) and X-Phos(0.14 g, 0.28 mmol) under nitrogen. (Note Color changed from purple tohunter green). The reaction was heated to reflux for 1 h and 20 min. Thereaction was cooled slowly to room temperature overnight. The mixturewas treated with 100 mL of brine and 100 mL of ethyl acetate andseparated the two layers. The aqueuous phase was extracted again withEtOAc (50 mL). Combined organic layers and passed through a plug offluoracil, dried over Na₂SO₄, decanted and removed the solvent byrotoevaporation to give crude product which was then purified by silicagel chromatography (25-50% EtOAc/Hexanes) to afford the desired product.

2,5-dioxopyrrolidin-1-yl ((1S,3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbonate (75c)

To a solution of (1R,3S)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-yl)amino)cyclohexanol,75b, (0.50 g, 1.00 mmol) and N,N-diisopropylethylamine (1.40 mL, 10.01mmol) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (1.28 g, 5.01mmol) in CH₃CN (4 mL) and stirred at room temperature overnight. Usedreaction mixture as is in next reaction. Using LCMS method m201:10-90CH3CN/H2O, formic acid modifier, 5 minutes, (C18); RT=3.73min,MH+=641.43 (strong).

Formation of (R)-(1S ,3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl3-fluoropyrrolidine-1-carboxylate (75d)

To (2,5-dioxopyrrolidin-1-yl) [(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbonate, 75c, (0.125 g, 0.195 mmol) already in acetonitrile was added(3R)-3-fluoropyrrolidine (0.445 g, 4.991 mmol) and the reaction mixturewas stirred at room temperature for 20 hours; The reaction was monitoredby HPLC until no more starting material was remaining. The reactionmixture was concentrated in vacuo and was carried on into the nextreaction without further purification.

Formation of (S)-(1S,3R)-3-05-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-yl)amino)cyclohexyl3-fluoropyrrolidine-1-carboxylate (1151)

To a solution of crude (R)-(1S,3R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl3-fluoropyrrolidine-1-carboxylate, 75d, (0.119 g, 0.019 mmol) in THF (2mL) was added 5 mL 2N LiOH (10 mmol). The reaction mixture was heated at50° C. for 2 hours. The mixture was diluted into aqueous saturatedammonium chloride (2 mL), and extracted with EtOAc (2×10 mL), dried oversodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified on the semi-prep HPLC, 10-70% CH₃CN/H₂O; Threeruns; homogeneous fractions were combined and the solvent removed undera stream of nitrogen and then removed residual solvent onroto-evaporator to afford 74 mg of the desired product: LCMS RT=2.15 min(M+H) 461.51.

Formation of 5-methylcyclohexane-1,3-diamine (76a)

The 3-methyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146ml) and treated with 6N HCl (22.5 ml, 135.0 mmol) and 5% Rhodium onAlumina (1.9 g, 0.9 mmol). The mixture was charged to 105 atm ofHydrogen and heated to 100° C. for 19 hours. The reaction was cooled andfiltered through celite and concentrated to dryness to give5-methylcyclohexane-1,3-diamine dihydrochloride (12.9 g, 64.5 mmol) as aracemic mixture. The salt (6.5 g, 32.5 mmol) was dissolved in isopropylalcohol (100 ml) and acetonitrile (100 ml) and treated with potassiumcarbonate (25.2 g, 182.0 mmol). The mixture was stirred at roomtemperature overnight, filtered thru celite, and concentrated in vacuoto afford 2.2 g of 5-methylcyclohexane-1,3-diamine as a racemic brownoil: LCMS RT=0.41 (M+1) 128.9.

Formation ofN¹-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine(76b)

To a solution of 5-methylcyclohexane-1,3-diamine, 76a, (2.2 g, 17.2mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added2,4-dichloro-5-fluoropyrimidine (1.4 g, 8.6 mmol). The mixture wasstirred at room temperature overnight, concentrated to dryness, andpurified on silica gel eluted with 1-20% methanol/dichloromethane, togive 0.6 g of racemicN¹-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine: ¹HNMR (300 MHz, MeOD) δ 7.85 (d, J=3.5 Hz, 1H), 4.07 (ddd, J=11.9, 7.9,4.1 Hz, 1H), 3.54 (qd, J=11.3, 4.2 Hz, 1H), 2.82 (tt, J=11.4, 3.7 Hz,1H), 2.16 (dd, J=15.0, 13.0 Hz, 1H), 1.89 (t, J=13.4 Hz, 2H), 1.50 (dd,J=76.0, 21.9 Hz, 2H), 1.10 (dt, J=17.9, 9.0 Hz, 1H), 0.99 (dd, J=8.5,5.0 Hz, 3H), 0.81 (ddd, J=23.8, 12.0, 8.2 Hz, 1H); LCMS RT=1.24 (M+1)259.1.

Formation of(3S)-N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)—5-methylcyclohexyl)-3-fluoropyrrolidine-1-carboxamide(76c)

To a solution ofN¹-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine,76b, (0.14 g. 0.54 mmol) in THF (2.5 ml) was added carbonyldiimidazole(0.10 g, 0.60 mmol) and ^(i)Pr₂NEt (0.28 mL, 1.62 mmol). The reactionwas aged 2 hours at room temp, and treated with (S)-3-fluoropyrrolidinehydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at roomtemperature for 2 days and then concentrated to dryness to afford 202 mgof(3S)-N-(342-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3-fluoropyrrolidine-1-carboxamidewhich was used without purification: LCMS RT=2.46 (M+1) 374.2, (M−1)372.

Formation of(3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide(76d)

To a solution of(3S)-N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methyl-cyclohexyl)-3-fluoropyrrolidine-1-carboxamide,)0(c,(0.101 g, 0.270 mmol) in 2-methyltetrahydrofuran (4 ml) was addedpotassium phophate (0.090 g, 0.950 mmol) in water (1.2 ml), x-phos(0.027 g, 0.057 mmol), and Pd₂dba₃ (0.015 g, 0.016 mmol). The reactionwas heated in a microwave at 120° C., for 20 minutes, and the organicphase was filtered thru a pad of florisil and the filtrate concentratedin vacuo. The crude was purified on silica gel eluted with EtOAc toafford 127 mg of racemic(3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide:LCMS RT=3.58 (M+1) 628.3, (M−1) 626.

Formation of (S)-3-fluoro-N-((1R, 3S,5R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide(76e)

To a solution of(3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide,76d, (0.090 g, 0.143 mmol) in MeOH (2.5 ml) was added 25% sodiummethoxide in methanol (2 ml). The reaction was stirred at roomtemperature for 30 minutes and quenched with aqueous saturated NH₄Cl.The methanol was removed in-vacuo and the residue was extracted withEtOAc and water. The organics were dried over sodium sulfate andconcentrated to dryness. The resulting crude racemate was purified bySFC separation on a chiral column. The second peak was concentrated invacuo to afford 32 mg of enantiomerically pure (S)-3-fluoro-N-((1R, 3S,5R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3—b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamideas a white solid: LCMS RT=1.89 (M+1) 474.2, (M−1) 472.4; SFC RT=3.2min., 15% MeOH @ 5 mL/min on an ODH (4.6*100), 100 bar, 35 C, 220 nm; ¹HNMR (300 MHz, DMSO) δ 12.26 (s, 1H), 8.41 (dd, J=9.9, 2.8 Hz, 1H),8.32-8.18 (m, 2H), 8.14 (d, J=4.0 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 6.02(d, J=7.9 Hz, 1H), 5.28 (d, J=53.6 Hz, 1H), 4.35-4.00 (m, 1H), 3.81-3.09(m, 12H), 2.24-1.77 (m, J=41.2, 26.1, 10.6 Hz, 4H), 1.74-1.51 (m, 1H),1.51-1.22 (m, 1H), 1.14-0.70 (m, 4H).

Formation of (1R, 5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime (77a)

To a solution of (1S, 5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35mmol) in ethanol (70 mL) was added O-methylhydroxylamine hydrochloride(2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reactionmixture to 80° C. for 4 hours. Removed solvent under reduced pressure.Diluted residue with 1N HCl and extracted twice with ether. The combinedorganic phases were washed with aqueous saturated NaHCO₃, dried (MgSO₄),filtered, concentrated in vacuo to afford 3.36 g of a colorless oil(mixture of oxime isomers) that was used without further purification.

Formation of (1R, 3S,5R)-2-(methoxyimino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carbaldehyde(77b)

To a cold (−78° C.) solution of (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime, 77a, (1.27 g,7.59 mmol) in THF (33 mL) was added dropwise a solution ofn-butyllithium (3.34 mL of 2.5 M solution in hexanes, 8.35 mmol). Afterstirring the mixture 20 min at −78° C. ethyl formate (0.61 mL, 7.59mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 3 hours and then quenched by pouring into aqueous saturated NaHCO₃solution. The mixture was extracted with EtOAc. The organic phase wasdried (MgSO₄), filtered and concentrated in vacuo. The resulting residuewas purified via silica gel chromatography (0-20% EtOAc/Hexanesgradient) to afford 810 mg yellow oil: LCMS RT=3.54 (M+H) 196.28.

Formation of (1R, 3S,5R)-3-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime (77c)

To a solution of (1R, 3S, 5R)-2-(methoxyimino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carbaldehyde, 77b, (0.70 g, 3.58 mmol) in methanol (15mL) was added sodium borohydride (0.16 g, 4.30 mmol). After stirring atroom temperature for 30 minutes, the reaction was diluted into aqueoussaturated NaHCO₃ solution and extracted with EtOAc. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The resultingresidue was purified via silica gel chromatography (0-50% EtOAc/Hexanesgradient) to afford 330 mg of the desired alcohol as mixture of oximeisomers.

Formation of (1R, 3S,5R)-3-(((tert-butyldiphenylsilypoxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-one0—methyl oxime (77d)

To a solution of (1R, 3S,5R)-3-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]-heptan-2-one O-methyloxime, 77c, (0.32 g, 1.60 mmol) in DMF (6 mL) was addedtert-butylchlorodiphenylsilane (0.55 g, 2.00 mmol) and imidazole (0.22g, 3.20 mmol). The reaction mixture was stirred at room temperature for18 hours. The reaction was diluted into aqueous saturated NH₄Cl solutionand extracted twice with Et₀Ac. The combined organic phases were washedtwice with brine, dried (MgSO₄), filtered and concentrated in vacuo. Theresulting residue was purified via silica gel chromatography (0-15%EtOAc/Hexanes gradient) to afford 200 mg of one oxime isomer and 197 mgof second oxime isomer.

Formation of (1R, 3S,5R)-3-(((tert-butyldiphenylsilypoxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine(77e)

To a solution of (1R, 3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-oneO-methyl oxime, 77d, (0.20 g, 0.46 mmol) in THF (3 mL) was addedborane-THF (1.38 mL of 1 M solution, 1.38 mmol). The reaction was heatedto 75° C. for 18 hours. The mixture was diluted into 1N NaOH (50 mL) andextracted twice with EtOAc. The combined organic phases were dried(MgSO₄), filtered and concentrated in vacuo to afford 178 mg of acolorless oil that was used without further purification: LCMS RT=2.53(M+H) 408.54.

Formation of N-((1R, 2S, 3S,5R)-3-(((tert-butyldiphenylsilypoxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine(77f)

To a solution of (1R, 3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine,77e, (0.20 g, 0.46 mmol) and5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine(0.11 mL, 0.61 mmol). The reaction was heated to 75° C. for 18 hours.The mixture was diluted into aqueous saturated NH₄Cl solution andextracted twice with EtOAc. The combined organic phases were washedtwice with brine, dried (MgSO₄), filtered and concentrated in vacuo. Thecrude residue was purified via silica gel chromatography (0-5%MeOH/CH₂Cl₂ gradient) to afford 78 mg of the desired product.

Formation of ((1R, 2S, 3S,5R)-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methanol(1229)

To a solution of N-((1R, 2S, 3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine,77f, (0.037 g, 0.046 mmol) in acetonitrile (1.1 mL) was added HCl (0.221mL of a 4 M solution in dioxane, 0.883 mmol). The mixture was heated to70° C. for 18 h, during which a precipitate formed. The reaction wasconcentrated in vacuo and triturated three times with CH₃CN to afford 4mg of the desired product as a white solid: ¹H NMR (300.0 MHz, MeOD) δ8.72-8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.2Hz, 1H), 4.71 (d, J=6.3 Hz, 1H), 3.67-3.57 (m, 2H), 2.33-2.26 (m, 1H),2.10 (m, 1H), 1.78-1.70 (m, 1H), 1.28-1.25 (m, 7H) and 1.19 (s, 3H) ppm;LCMS RT=3.13 (M+H) 416.42.

Influenza Antiviral Assay

Antiviral assays were performed using two cell-based methods:

A 384-well microtiter plate modification of the standard cytopathiceffect (CPE) assay method was developed, similar to that of Noah, et al.(Antiviral Res. 73:50-60, 2006). Briefly, MDCK cells were incubated withtest compounds and influenza A virus (A/PR/8/34), at a low multiplicityof infection (approximate MOI=0.005), for 72 hours at 37° C., and cellviability was measured using ATP detection (CellTiter Glo, PromegaInc.). Control wells containing cells and virus show cell death whilewells containing cells, virus, and active antiviral compounds show cellsurvival (cell protection). Different concentrations of test compoundswere evaluated, in quadruplicate, for example, over a range fromapproximately 20 μM to 1 nM. Dose-response curves were prepared usingstandard 4-parameter curve fitting methods, and the concentration oftest compound resulting in 50% cell protection, or cell survivalequivalent to 50% of the uninfected wells, was reported as the IC₅₀.

A second cell-based antiviral assay was developed that depends on themultiplication of virus-specific RNA molecules in the infected cells,with RNA levels being directly measured using the branched-chain DNA(bDNA), hybridization method (Wagaman et al, J. Virol Meth, 105:105-114,2002). In this assay, cells are initially infected in wells of a 96-wellmicrotiter plate, the virus is allowed to replicate in the infectedcells and spread to additional rounds of cells, then the cells are lysedand viral RNA content is measured. This assay is stopped earlier thatthe CPE assay, usually after 18-36 hours, while all the target cells arestill viable. Viral RNA is quantitated by hybridization of well lysatesto specific oligonucleotide probes fixed to wells of an assay plate,then amplification of the signal by hybridization with additional probeslinked to a reporter enzyme, according to the kit manufacturer'sinstructions (Quantigene 1.0, Panomics, Inc.). Minus-strand viral RNA ismeasured using probes designed for the consensus type A hemagglutinationgene. Control wells containing cells and virus were used to define the100% viral replication level, and dose-response curves for antiviraltest compounds were analyzed using 4-parameter curve fitting methods.The concentration of test compound resulting in viral RNA levels equalto that of 50% of the control wells were reported as EC₅₀.

Virus and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34American Type Culture Collection) were maintained in Dulbecco's ModfiedEagle Medium (DMEM) supplemented with 2 mM L-glutamine, 1,000U/mlpenicillin, 1,000 ug/ml streptomycin, 10 mM HEPES, and 10% fetal bovinemedium. For the CPE assay, the day before the assay, cells weresuspended by trypsinization and 10,000 cells per well were distributedto wells of a 384 well plate in 50 μl. On the day of the assay, adherentcells were washed with three changes of DMEM containing lug/mlTPCK-treated trypsin, without fetal bovine serum. Assays were initiatedwith the addition of 30 TCID₅₀ of virus and test compound, in mediumcontaining 1 μg/ml TPCK-treated trypsin, in a final volume of 50 μl.Plates were incubated for 72 hours at 37° C. in a humidified, 5% CO₂atmosphere. Alternatively, cells were grown in DMEM+fetal bovine serumas above, but on the day of the assay they were trypsinized, washed 2times and suspended in serum-free EX-Cell MDCK cell medium (SAFCBiosciences, Lenexa, Kans.) and plated into wells at 20,000 cells perwell. These wells were then used for assay after 5 hours of incubation,without the need for washing.

Influenza virus, strain A/PR/8/34 (tissue culture adapted) was obtainedfrom ATCC (VR-1469). Low-passage virus stocks were prepared in MDCKcells using standard methods (WHO Manual on Animal Influenza Diagnosisand Surveillance, 2002), and TCID₅₀ measurements were performed bytesting serial dilutions on MDCK cells in the 384-well CPE assay format,above, and calculating results using the Karber method.

Mean IC₅₀ values (mean all) for certain specific compounds aresummarized in Tables 1-5:

A: IC₅₀ (mean all)<5 μM;

B 5 μM≤IC₅₀ (mean all)≤20 μM;

C IC₅₀ (mean all)>10 μM;

D IC₅₀ (mean all)>20 μM;

E IC₅₀ (mean all)>3.3 μM.

Mean EC₅₀ values (mean all) for certain compounds are also summarized inTables 1-5:

A: EC₅₀ (mean all)<5 μM;

B 5 μM≤EC₅₀ (mean all)≤10 μM;

C EC₅₀ (mean all)>3.3 μM;

D EC₅₀ (mean all)>10 μM.

As can be seen in Tables 1-5, a lot of compounds of the invention showedpositive effect on the survial of the A/PR/8/34 infected cells, andinhibitory effect on the replication of A/PR/8/34 influenza virus.Exemplary IC₅₀ and EC₅₀ values are as follows: Compound 428 had 0.03 μMof IC₅₀; Compound 895 had 0.0008 μM of IC₅₀ and 0.001 μM of EC₅₀;Compound 833 had 5.6 μM of IC₅₀ and 3.5 μM of EC₅₀.

TABLE 1 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of FIG. 3: Comp. Nos.IC₅₀ EC₅₀ LCMS_Plus LCMS_RT NMR 1 A 411.38 2.69 H NMR (300.0 MHz, DMSO)d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H),8.18-8.16 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 6.33 (t, J = 4.4 Hz,0.25H), 6.15 (t, J = 4.3 Hz, 0.5H), 5.96 (t, J = 4.3 Hz, 0.25H), 4.22(d, J = 7.6 Hz, 1H), 3.13 (d, J = 11.2 Hz, 1H), 2.88 (m, 1H), 2.81 (ddd,J = 15.5, 4.2, 4.2 Hz, 2H), 2.30-2.20 (m, 2H), 1.98 (m, 1H), 1.72-1.61(m, 2H) and 1.49-1.36 (m, 1H) ppm 2 475 3.58 1H NMR (CD3OD): 1.1-1.3(3H, m), 1.40-1.50 (3H, m), 1.55-2.10 (4H, m), 2.40-2.45 (1H, m),3.3-3.5 (2H, m), 3.75-4.10 (4H. m). 5.4-5.5 (1H. m), 8.05-8.20 (3H, m),8.70-8.80 (1H, m) 3 446.14 2.96 1H NMR (DMSO): 1.39 (4H, m), 1.542 (1H,m), 1.74 (2H, m), 2.33 (1H, m), 2.61 (1H, m), 2.88 (1H, m), 4.18 (1H,m), 4.37 (1H, m), 5.21 (1H, m), 6.84 (2H, d), 7.33 (2H, d), 7.60 (2H,m), 8.23 (3H, m), 8.63 (1H, d), 12.33 (1H, s) 4 D 327 1.2 500 MHz,MeOD-d4: 8.83(dd, 1H), 8.45(s, 1H), 8.42(dd, 1H), 8.32(d, 1H), 7.65(d,2H), 7.42(dd, 1H), 7.18(d, 2H), 4.55(m, 1H), 3.4(m, 1H), 2.3(s, 3H),2.2(m, 2H), 1.95(m, 2H), 1.5(m, 4H) 5 385.3 1.74 6 401.3 1.68 7 D 371.11.63 8 421.1 1.82 H NMR (500 MHz, DMSO-d6) 12.98 (s, 1H), 9.24 (s, 1H),8.80 (s, 1H), 8.60 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 7.0Hz, 1H), 6.65 (d, J = 6.7 Hz, 1H), 3.81-3.43 (m, 4H), 2.36 (t, J = 1.8Hz, 1H), 2.19 (d, J = 10.1 Hz, 1H), 1.62 (s, 6H), 0.00 (TMS) 9 403.11.69 H NMR (500 MHz, DMSO-d6) 13.01 (s, 1H), 9.40 (s, 1H), 8.85 (d, J =6.9 Hz, 1H), 8.63 (s, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 7.0Hz, 1H), 6.66 (s, 1H), 5.29-5.05 (m, 1H), 3.86- 3.16 (m, 4H), 1.65 (d, J= 10.6 Hz, 2H), 1.60 (s, 6H), 0.00 (TMS) 10 403.1 1.74 H NMR (500 MHz,DMSO-d6) 12.99 (d, J = 6.1 Hz, 1H), 9.39 (s, 1H), 8.84 (s, 1H), 8.62 (s,1H), 8.38 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.29- 5.05(m, 1H), 3.87-3.15 (m, 4H), 1.64 (d, J = 10.8 Hz, 2H), 1.59 (s, 6H),0.00 (TMS) 11 A A 362.2 1.8 12 D 376.2 1.9 13 A 362.2 1.8 14 B A (400MHz, DMSO-d6): 12.80 (s, exchanged with D2O, 1H), 8.82 (d, J = 2.4 Hz,1H), 8.28 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.14 (d, J =4.0 Hz, 1H), 7.46 (br. d, J = 6.4 Hz, exchanged with D2O, 1H), 4.82 (d,J = 3.6 Hz, 1H), 4.27 (quintet, J = 6.4 Hz, 1H), 4.14 (quintet, J = 5.6Hz, 1H), 2.20-2.10 (m, 1H), 1.94-1.77 (m, 1H), 1.77-1.70 (m, 2H),1.65-1.50 (m, 2H). 15 B A 461.3 2.68 H NMR (300 MHz, DMSO-d6) 12.32 (s,1 H), 8.72 (d, J = 2.5 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 8.19-8.15(m, 1 H), 7.75 (d, J = 5.3 Hz, 1 H), 3.89 (s, 1 H), 3.69 (s, 1 H),3.53-3.45 (m, 2 H), 3.45 (s, 1H), 2.89-2.49 (m, 2 H), 1.90-1.68 (m, 3H), 1.28 (m, 2 H), 1.28 (s, 9 H) 16 D A 461.3 2.63 H NMR (300 MHz,DMSO-d6) 12.31 (s, 1 H), 8.71 (d, J = 2.5 Hz, 1 H), 8.27 (d, J = 2.4 Hz,1 H), 8.20-8.15 (m, 2 H), 7.74 (d, J = 5.9 Hz, 1 H), 3.88 (d, J = 3.8Hz, 2 H), 3.71 (d, J = 11.3 Hz, 1 H), 3.53-3.35 (m, 3 H), 2.86 (t, J =10.4 Hz, 1 H), 1.90 (s, 2 H), 1.68 (d, J = 9.1 Hz, 1 H), 1.41 (s, 2 H),1.28 (s, 9 H), 17 B A 445.3 3.1 18 B A 443.3 2.9 19 D 503.4 2.8 20 B460.4 3 21 A A 451.3 2.9 22 A A 486.3 2.9 23 A A 419.3 2.8 24 D 463.22.8 25 A A 490.3 2.6 26 A A 476.3 2.5 27 A A 446.4 2.7 28 D A 461.4 3.329 B 418.3 2.4 30 B A 457.3 3.1 31 A A 411.2 2.22 (400 MHz, DMSO-d6):12.73 (s, exchanged with D2O, 1H), 8.85 (s, 1H), 8.65 (d, J = 5.6 Hz,1H), 8.37 (d, J = 6.8 Hz, 1H), 8.03-7.89 (m, 4H, addition of D2O changedto d, J = 7.6 Hz, 1H), 4.03-3.98 (m, 1H), 3.60- 3.50 (m, 1H), 2.18-1.95(m, 2H), 1.77- 1.23 (m, 6H). 32 A A 417.4 2.6 33 A A 433.3 3 34 A 431.42.8 35 D 447.4 3.2 36 A A 439.3 2.7 37 A A 403.3 2.4 38 A A 457.4 3.1 39A A 444.4 2.6 40 D 481.3 2.5 41 A A 429.3 2.7 42 D 459.3 3.1 43 D 460.32.4 44 A A 471.3 2.8 45 A A 433.3 2.4 46 D 446.3 2.5 47 A A 480.3 2.4 48D 471.3 2.4 49 A A 429.3 2.7 50 D 469.3 2.3 51 A A 472.9 1.7 52 A A441.3 1.9 53 B 475.3 1.8 54 B 477.3 1.7 55 A A 501.3 2.5 56 A A 479.32.9 57 A A 443.3 2.8 58 A 483.3 2.9 59 A A 429.3 2.7 60 A A 527 3.2 61 AA 465.3 2.8 62 A A 531.3 3.1 63 D 539.3 3.2 64 B A 519.3 3.1 65 A A519.2 3.1 66 A A 515.3 3.2 67 A A 579.2 3.3 68 B A 481.4 3.2 69 A A511.3 3.2 70 A A 515.3 3.3 71 B 495.3 3.4 72 B 549.3 3.5 73 B 499.3 3.374 A A 445.2 3.1 75 A A 498.3 3 76 A A 510.3 2.9 77 B 522.3 2.8 78 A A494.3 3 79 B 548.3 3.3 80 A A 503.3 1.9 81 A A 529.3 2 82 D 511.3 1.6 83D 473.4 1.6 84 A A 499.4 2 85 B A 501.3 2.1 86 A A 501.3 2.1 87 A A501.3 2.1 88 A A 561.3 2 89 A A 507.2 2.1 90 A A 519.2 2.1 91 A A 505.31.8 92 A A 437.2 2.7 93 A A 451.2 2.9 94 A A 495.3 2.9 95 A A 471.3 3.296 B 535.2 2.9 97 A A 471.2 2.9 98 A A 497.3 2.9 99 A A 457.3 3.1 100 AA 471.3 3.1 101 A A 467.2 2.5 102 A A 455.3 2.7 103 A 509.3 2.8 104 A A485.3 2.8 105 A A 445.3 3 106 A A 509.3 3 107 A A 521.3 3.2 108 A A501.3 2.8 109 A A 525.3 2.7 110 A A 461.3 2.5 111 A A 403.2 2.4 112 A A494.3 3 113 A A 495.3 2.8 114 D 442.5 1.6 115 D 377.2 1.286 (400 MHz,DMSO-d6): 12.99 (m, exchanged with D2O, 1H), 9.01 (m, exchanged withD2O, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.32 (overlapped s,1H), 8.29 (overlapped br.s, exchanged with D2O, 1H), 7.50- 7.20 (m,exchanged with D2O, 1H), 4.47-4.40 (m, 1H), 3.53-3.45 (m, 1H), 2.19 (br.d, J = 10.0 Hz, 1H), 2.08 (br. d, J = 10.4 Hz, 1H), 1.84 (br. d, J =10.4 Hz, 2H), 1.60-1.29 (m, 4H). 116 D 357.2 3.267 (400 MHz, DMSO-d6):12.70 (br. hump, exchanged with D2O, 1H), 8.72 (s, 1H), 8.36 (s, 1H),8.20-8.06 (overlapped hump, exchanged with D2O, 1H, +a s for animpurity), 7.47 (d, J = 7.6 Hz, 1H), 7.35- 7.0(overlapped m, exchangedwith D2O, 2H), 7.10 (overlapped d, J = 8.0 Hz, 1H), 4.39-4.35 (m, 1H),3.16-3.10 (m, 1H), 2.28 (s, 3H), 2.18-1.35 (m, 8H). 117 A A 486.3 2.8118 B 504.2 2.6 119 A A 445.4 3.1 120 A A 552.4 3.2 121 D 446.4 2.2 122A A 443.3 2.9 123 B A 461.5 3.4 124 A A 439.3 3.1 125 A A 490.4 2.6 126A A 451.3 2.9 127 A A 457.3 3.1 128 A A 460.4 3 129 A A 486.4 2.9 130 A500.6 2 131 A A 462.7 1.6 132 D 449.7 2.2 133 D 405.3 2.3 134 B 457.33.1 135 D 433.4 2.5 136 D 469.3 3.2 137 D 465.4 3.1 138 D 459.3 2.8 139D 465.3 3.2 140 D 459.3 2.9 141 D 433.5 1.4 142 A A 541.5 2.8 143 A A479.4 2.9 144 D A 533.3 3 145 A A 507.3 2.9 146 A A 533.3 3 147 A A533.3 3.2 148 A A 509.3 3 149 A A 509.4 3 150 B 557.3 3.2 151 A A 501.42.9 152 A A 501.2 2.9 153 A A 495.3 2.8 154 B A 525.4 2.8 155 A A 479.42.9 156 A A 499.4 3 157 A A 493.1 2 158 A 510 2 159 B A 418.3 2.3 160 DA 451.4 2.1 161 D A 463.4 2.8 162 D A 480.3 2.8 163 B A 467.4 3.1 164 DA 443.5 3 165 D 472.5 2.8 166 B A 419.5 2.9 167 D B 444.4 2.7 168 B A432.3 2.6 169 D B 490.5 2.7 170 D A 446.4 2.7 171 D B 433.3 3 172 D495.5 3.2 173 A A 403.3 2.5 174 D 495.6 2.8 175 A A 418.5 2.4 176 D A467.3 2.3 177 A A 444.4 2.7 178 A A 446.4 2.8 179 A A 403.4 2.5 180 A A451.3 2.9 181 B A 443.4 3 182 A A 432.3 2.6 183 B A 433.3 3 184 D 495.52.7 185 A A 463.4 2.8 186 A A 472.4 2.8 187 A A 480.3 2.8 NMR 1H(CDCl3): 8.7 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 4.7 (m,1H), 4.2 (m, 1H), 1.3-3.7 (m, 15H). 188 A A 419.4 2.9 189 A A 490.5 2.7190 B 495.4 3.1 191 A A 446.3 2.7 192 A A 460.4 2.9 193 B A 474.4 3.1194 A A 431.2 2.9 195 B 513.2 2.5 196 A A 432.1 2.6 197 A A 446.2 2.7198 A A 453.1 2.9 199 A A 439.1 2.8 200 A A 453.1 2.9 201 D A 481.1 2.6202 A A 478.2 2.7 203 A A 458.2 2.8 204 A A 462.2 2.5 205 A A 476.2 2.6206 A 327.2 1.85 H NMR (300.0 MHz, DMSO) d 12.14 (s, 1H), 8.66 (d, J =8.0 Hz, 1H), 8.29- 8.22 (m, 3H), 7.81 (s, 2H), 7.28- 7.19 (m, 2H), 4.55(s, 1H), 3.74 (s, 1H) and 1.92-1.49 (m, 8H) ppm 207 A A 328.2 2.22 208 AA 417.2 1.9 209 A A 483.1 2 210 D B 533.1 2.2 211 B 369.3 2.27 212 A383.3 2.42 213 D 417.3 2.45 214 D 447.3 2.35 215 D 384.3 2.27 216 D355.3 2.08 217 B 355.3 1.93 218 A A 369.4 2.08 219 D 383.3 2.23 220 A384.3 2.12 221 B 417.3 2.34 222 D 447.3 2.25 223 B 369.3 2.12 224 B383.3 2.27 225 B 397.4 2.38 226 A 431.3 2.49 227 B 461.3 2.49 228 B398.3 2.31 229 D 370.3 2.05 230 D 384.3 2.23 231 D 398.3 2.35 232 B432.3 2.6 233 B A 370.3 1.9 234 B 384.3 2.04 235 B 398.3 2.2 236 B 432.42.38 237 B 384.3 2.05 238 B 398.3 2.19 239 D 369.3 2.27 240 D 383.3 2.43241 B 417.3 2.48 242 D 447.3 2.45 243 D 384.4 2.26 244 D 355.3 1.97 245B 369.3 2.08 246 D 383.3 2.19 247 D 384.3 2.15 248 D 370.3 2.05 249 D384.3 2.23 250 D 396.5 2.36 251 B 432.3 2.64 252 D 370.4 1.89 253 D382.4 1.99 254 D 398.3 2.12 255 B 432.4 2.37 256 B 369.3 2.2 257 B 383.32.31 258 B 397.3 2.46 259 B 431.3 2.42 260 D 461.3 2.36 261 B 398.3 2.35262 D 412.4 2.27 263 B 446.3 2.6 264 B 384.3 2.12 265 D 398.4 2.23 266 B412.3 2.38 267 B 446.4 2.6 268 B 369.3 2.08 269 B 383.3 2.27 270 B 397.32.42 271 B 431.4 2.49 272 D 461.3 2.46 273 B 398.3 2.31 274 B 384.3 2.05275 B 398.4 2.2 276 D 412.4 2.31 277 A A 328.2 1.56 278 D 465.1 2.4 279A A 443.2 2.1 280 A A 471.2 2.1 281 A A 455.2 2.1 282 A A 486.1 2 283 B578.2 2.4 284 A A 458.2 2 285 D 498.2 1.6 286 D 516.2 1.7 287 D 488.21.9 288 B 488.2 1.9 289 D 501.2 1.6 290 B 529.2 1.8 291 D 488.2 1.9 292D 481.2 1.6 293 A A 493.2 3.1 294 D 485.2 3.3 295 A A 431.2 2.9 296 B(400 MHz, CDCl3): 8.85 (d, J = 2.0 Hz, 1H), 8.80 (br s, 1H), 8.29 (d, J= 2.4 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 3.2 Hz, 1H), 6.19(br. hump, 1H), 5.16 (qunitet, J = 7.6 Hz, 1H), 3.78-3.50 (series of m,4H), 2.16-1.91(series of m, 4H), 1.58 (d, J = 7.6 Hz, 3H) 297 B (400MHz, CDCl3): 8.95 (br. hump, exchanged withy D2O, 1H), 8.83 (d, J = 2.0Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, addtion of D2Ochanged to s, 1H), 8.07 (d, J = 3.2 Hz, 1H), 6.40(br. d, J = 5.6 Hz,1H), 5.16 (qunitet, J = 6.8 Hz, addition of D2O changed to q, J = 6.8Hz, 1H), 3.07- 3.50 (series of m, 4H), 1.70-1.60 (series of m, 6H), 1.55(d, J = 6.4 Hz, 3H) 298 D (400 MHz, CDCl3): (400 MHz, CDCl3): 9.15 (br.hump, exchanged with D2O, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.30 (d, J =2.4 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 3.2 Hz, 1H), 6.29(d, J 6.4 Hz, exchanged with D2O, 1H), 5.30 (quintet, J = 6.8 Hz,addtion of D2O changed wtih q, J = 6.8 Hz, 1H), 3.90-3.80 (m, 4H),2.60-2.40 (m, 4H), 2.33 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H). 299 D (400MHz, CDCl3): 9.15 (br. hump, exchanged with D2O, 1H), 8.83 (br. s, 1H),8.30 (br. s, 1H), 8.11-8.07 (m, 2H), 6.99 (br. s, exchanged with D2O,1H), 5.40-5.30 (m, 1H), 3.90- 3.40 (m, 8H), 2.14 (s, 3H), 1.57 (doverlapped with moisture, J = 7.2 Hz, 3H). 300 B (400 MHz, CDCl3): 9.10(br. hump, exchanged with D2O, 1H), 8.83 (br. s, 1H), 8.30 (br. s, 1H),8.11 (br. s, 1H), 8.09 (d, J = 1.2 Hz, 1H), 6.24 (br. d, J = 5.2 Hz,exchanged with D2O, 1H), 5.30 (quintet, J = 7.2 Hz, addtion of D2Ochanged wtih q, J = 6.8 Hz, 1H), 3.90-3.80 (m, 8H), 1.54 (overlaped d, J= 7.2 Hz, 3H). 301 B 460.4 1.712 (400 MHz, DMSO-d6, 7): 8.69 (d, J = 2.4Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 3.6 Hz, 1H), 8.16 (br.s,1H), 5.25-5.15 (m, 1H), 3.82-3.25 (m, 8H), 1.93 (br. s, 3H), 1.80-170(m, 2H), 1.43 (d, J = 6.8 Hz, 3H). 302 B (400 MHz, DMSO-d6): 8.56 (d, J= 2.0 Hz, 1H), 8.31 (br. s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.07 (d, J =2.8 Hz, 1H), 5.17 (dq, J = 7.6, 6.8 Hz, 1H), 3.77-3.70 (m, 1H),3.67-3.49 (m, 3H), 2.10-2.01 (m, 2H), 1.95-1.90 (m, 2H), 1.57 (d, J =6.8 Hz, 3H). 303 D (400 MHz, DMSO-d6): 9.375 (br. hump, exchanged withD2O, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.13 (d, J= 2.0 Hz, 1H), 8.07 (d, J = 3.2 Hz, 1H), 6.36 (br. d, J = 6.8 Hz, 1H),5.33 (q, J = 6.8 Hz, 1H), 3.71-3.61 (m, 4H), 1.71-1.61 (m, 6H), 1.56 (d,J = 6.4 Hz, 3H). 304 D (400 MHz, DMSO-d6): 9.09 (s, exchanged with D2O,1H), 8.83 (d, J = 2.0 Hz, 1H), 8.31 (br. s, 1H), 8.12 (d, J = 2.8 Hz,1H), 8.08 (d, J = 3.6 Hz, 1H), 6.28 (d, J = 6.8 Hz, exchanged with D2O,1H), 5.31 (dq J = 7.2, 6.8 Hz, 1H), 3.80-3.70 (m, 4H), 2.55-2.40 (m,4H), 2.34 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H). 305 A A 460.3 2.58 306 A A453.2 2.5 307 D 462.3 2.418 (400 MHz, CDCl3): 8.90 (br. s, exchangedwith D2O, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.10(s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 6.20 (br. s, exchanged with D2O, 1H),5.40-5.35(m, 1H), 3.74 (s, 3H), 3.90-3.40 (series of m, 8H), 1.58 (d, J= 7.6 Hz, 3H) 308 D (400 MHz, CDCl3): 9.11 (s, exchanged with D2O, 1H),8.80 (s, 1H), 8.31 (s, 1H), 8.10-8.08 (m, 2H), 6.17 (br. s, exchangedwith D2O, 1H), 5.40-5.35 (m, 1H), 3.90-3.40 (series of m, 8H), 2.14 (s,3H), 1.59 (overlapped d, J = 6.4 Hz, 3H) 309 B (400 MHz, DMSO-d6): 12.07(s, exchanged with D2O, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4Hz, 1H), 8.18 (d, J = 3.6 Hz, 1H), 8.17 (overlapped br. s, 1H), 7.16(br. s, 1H), 5.20-5.05 (m, 1H), 3.90-3.40 (series of m, 8H), 2.56(overlapped s with DMSO-d6 signal, 3H), 1.43(br. s, 3H), 1.40-1.20 (m,2H) 310 D (400 MHz, CDCl3): 9.28 (s, exchanged with D2O, 1H), 8.81 (d, J= 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 3.3 Hz, 1H), 8.10(d, J = 2.4 Hz, 1H), 6.22 (br. d, J = 6.4 Hz, 1H), 5.32 (quiniet, 6.4Hz, addition of D2O changed to q, J = 6.4 Hz, 1H), 3.74 (s, 3H),3.68-3.49 (series of m, 8H), 1.57 (d, J = 6.4 Hz, 3H) 311 D (400 MHz,CDCl3): 9.04 (s, exchanged with D2O, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.29(br. d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 3.2 Hz,1H), 6.23 (br. d, J = 6.8 Hz, 1H), 5.31 (quiniet, J = 6.8 Hz, additionof D2O changed to q, J = 6.8 Hz, 1H), 3.68-3.49 (series of m, 8H), 1.57(d, J = 6.8 Hz, 3H) 312 A A (400 MHz, CDCl3): 9.72 (s, exchanged withD2O, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.13 (d, J= 2.0 Hz, 1H), 8.08 (d, J = 4.4 Hz, 1H), 6.07 (d, J = 7.6 Hz, exchangedwith D2O, 1H), 4.95 (qunitet, J = 7.2 Hz, 1H), 4.68 (q, J = 7.6 Hz, 1H),4.36 (d, J = 8.4 Hz, 1H), 4.18-4.07 (m, 2H), 2.40-2.30 (m, 2H), 1.54 (d,J = 7.2 Hz, 3H). 313 B A (400 MHz, DMSO-d6, 80° C.): 12.07 (s, exchangedwith D2O, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.21(d, J = 2.0 Hz, 1H), 8.17 (br. s, 1H), 7.14 (br. s, exchanged with D2O,1H), 5.20-5.10 (m, 1H), 3.70-3.50 (m, 8H), 1.54 (d, J = 7.2 Hz, 3H),1.95-1.80 (m, 2H) 314 B B (400 MHz, CDCl3): 9.80 (s, exchanged with D2O,1H), 8.83 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.13 (d, J =2.0 Hz, 1H), 8.08 (d, J = 4.4 Hz, 1H), 6.08 (d, J = 6.4 Hz, exchangedwith D2O, 1H), 4.95 (qunitet, J = 7.2 Hz, 1H), 4.68 (q, J = 7.6 Hz, 1H),4.36 (d, J = 8.0 Hz, 1H), 4.18-4.07 (m, 2H), 2.40-2.30 (m, 2H), 1.55 (d,J = 7.2 Hz, 3H). 315 B D (400 MHz, DMSO-d6, 80° C.): 12.08 (s, exchangedwith D2O, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.18(d, J = 2.0 Hz, 1H), 8.16 (br. s, 1H), 7.14 (br. d, J = 7.2 Hz,exchanged withD2O, 1H), 5.20-5.10 (m, 1H), 3.70-3.50 (m, 8H), 1.46 (d, J= 7.2 Hz, 3H), 1.95-1.80 (m, 2H) 316 B A 453.3 2.48 317 B A 415.1 2.7318 D A 431.1 2.9 319 D A 429.1 2.8 320 B B 433.1 2.5 321 B A 439.1 2.7322 D A 453.1 2.9 323 D A 446.2 2.7 324 B A 432.2 2.6 325 B A 429.2 2.7326 B A 445.2 3 327 A A 447.2 1.8 328 D 467.1 2.2 329 D 481.2 2.3 330 AA 501.1 2.2 331 A A 465.1 2.2 1H NMR (300.0 MHz, MeOD) d 8.83 (d, J =2.3 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 3.9Hz, 1H), 4.44 (m, 1H), 4.06 (dd, J = 9.2, 13.8 Hz, 1H), 3.77 (dd, J =6.3, 13.8 Hz, 1H), 3.71 (m, 1H), 2.47 (m, 1H), 1.87-1.66 (m, 6H) and1.00- 0.92 (m, 4H) ppm 332 A A 431.2 2 333 B 417.4 2.7 334 B 431.4 2.85335 D 457.3 3.14 336 D 465.4 3.03 337 B A 439.3 2.66 338 D 467.3 2.93339 B 446.3 2.85 340 A A 403.3 2.6 341 D 383.4 2.3 H NMR (300.0 MHz,DMSO) d 12.47 (s, 1H), 8.65 (d, J = 8.1 Hz, 1H), 8.49- 8.23 (m, 3H),7.61 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 4.7, 8.0 Hz, 1H), 4.39 (d, J =19.5 Hz, 2H), 2.10 (q, J = 7.6 Hz, 2H), 1.79-1.64 (m, 6H), 1.48 (d, J =6.4 Hz, 2H) and 0.91 (t, J = 7.6 Hz, 3H) ppm 342 D 397.4 2.48 343 D423.4 2.71 344 D 431.4 2.67 345 D 405.3 2.3 H NMR (300.0 MHz, DMSO) d12.47 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.45- 8.34 (m, 3H), 7.29 (dd, J= 4.8, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.47- 4.25 (m, 1H),4.05-3.89 (m, 1H), 2.80 (s, 3H), 1.95-1.62 (m, 6H) and 1.49-1.24 (m, 2H)ppm 346 D 433.3 2.56 H NMR (300.0 MHz, DMSO) d 12.41 (s, 1H), 8.65 (d, J= 7.8 Hz, 1H), 8.38- 8.33 (m, 3H), 7.28 (dd, J = 4.7, 7.9 Hz, 1H), 7.06(d, J = 8.1 Hz, 1H), 4.36 (s, 1H), 3.88 (s, 1H), 2.83 (t, J = 7.7 Hz,2H), 1.85-1.70 (m, 6H), 1.59 (q, J = 7.8 Hz, 2H), 1.47-1.24 (m, 2H) and0.82 (t, J = 7.4 Hz, 3H) ppm 347 D 412.4 2.41 H NMR (300.0 MHz, DMSO) d12.47 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.45- 8.34 (m, 3H), 7.29 (dd, J= 4.8, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.47- 4.25 (m, 1H),4.05-3.89 (m, 1H), 2.80 (s, 3H), 1.95-1.62 (m, 6H) and 1.49-1.24 (m, 2H)ppm 348 D 369.4 2.19 H NMR (300.0 MHz, DMSO) d 12.53 (s, 1H), 8.66 (d, J= 7.6 Hz, 1H), 8.43 (s, 1H), 8.39-8.36 (m, 2H), 7.91 (d, J = 7.9 Hz,1H), 7.32 (dd, J = 4.7, 7.9 Hz, 1H), 4.08-3.94 (m, 1H), 3.86 (d, J = 8.4Hz, 1H), 2.13 (d, J = 24.3 Hz, 1H), 1.95 (d, J = 10.2 Hz, 1H), 1.81-1.73 (m, 2H), 1.73 (s, 3H) and 1.43- 1.14 (m, 4H) ppm 349 D 417.3 2.74350 B 417.3 2.74 351 D 457.3 3.11 352 D 465.3 3.03 353 D 439.4 2.74 354D 467.3 3.04 355 D 446.3 2.81 356 D 383.4 2.33 357 D (400 MHz, CDCl3,75° C.): 12.07 (br. s exchanged with d2O, 1H), 8.69 (s, J = 2.4 Hz, 1H),8.25 (s, J = 4.0 Hz, 1H), 8.19 (s, J = 4.0 Hz, 1H), 8.15 (br. s, 1H),7.15 (br. s, exchanged with D2O, 1H), 5.20-5.10 (q, 1H), 3.62- 3.55 (m,8H), 3.03 (s, 3H), 1.76 (d, J = 2.4 Hz, 2H), 1.43-1.41 (d, J = 8.0 Hz,3H). 358 D 397.4 2.45 359 D 423.4 2.67 360 D 431.4 2.63 361 D 405.3 2.37H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.43-8.36 (m, 3H), 7.32 (dd, J = 4.7, 7.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H),4.16 (d, J = 9.3 Hz, 1H), 3.35 (d, J = 9.8 Hz, 1H), 2.91 (d, J = 8.9 Hz,3H), 2.12- 2.02 (m, 2H), 1.79-1.73 (m, 2H) and 1.64-1.15 (m, 4H) ppm 362D 433.3 2.63 H NMR (300.0 MHz, DMSO) d 12.43 (s, 1H), 8.68 (d, J = 7.9Hz, 1H), 8.38- 8.33 (m, 3H), 7.29 (dd, J = 4.7, 7.8 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 4.14 (d, J = 6.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.07-2.89(m, 2H), 2.07 (d, J = 12.6 Hz, 2H), 1.76 (d, J = 7.9 Hz, 2H), 1.61-1.33(m, 6H) and 0.90 (t, J = 7.4 Hz, 3H) ppm 363 D 431.3 2.88 364 D 457.33.11 365 D 465.3 3.03 366 A A 439.2 2.74 367 B 467.3 2.99 368 D 446.32.81 369 D 431.3 2.85 370 D 412.4 2.41 371 D 412.2 1.78 372 B B 424.21.87 373 B D 398.2 1.69 374 D 384.2 1.61 375 B B 412.2 1.8 376 B 327.141.46 377 D 313.33 1.38 378 D (300 MHz, DMSO-d6): 12.35 (br. s, exchangedwith D2O, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.21(s, 1H), 8.17 (d, J = 3.9 Hz, 1H), 7.80 (br. s, exchanged with D2O, 1H),7.10 (s, exchanged with D2O, 1H), 2.27-2.11 (m, 2H), 1.96 (m, 2H), 1.55(m, 2H), 1.40-1.18 (m, 3H). 379 B A 361.3 2.3 1H NMR (300.0 MHz, MeOD) d8.72 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.11-8.07 (m, 2H),4.94 (t, J = 9.3 Hz, 1H), 3.64-3.51 (m, 2H), 2.97 (s, 3H), 2.68-2.54 (m,1H) and 2.37-2.23 (m, 1H) ppm 380 B 347.3 2.27 1H NMR (300.0 MHz, MeOD)d 8.79 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.07(d, J = 3.9 Hz, 1H), 4.91 (dd, J = 8.7, 10.6 Hz, 1H), 3.61-3.46 (m, 2H),2.68-2.58 (m, 2H) and 2.48-2.31 (m, 1H) ppm 381 A A 439.3 2.72 382 A A453.3 2.86 383 A A 507.3 3.01 384 A 439.3 2.72 385 A 453.3 2.82 386 A465.3 2.9 387 B 507.2 2.49 388 D 453.4 1.84 389 A A 425.3 1.8 390 A A467.3 2.1 391 A A 451.3 1.9 392 A A 493.5 2.3 393 A A 439.3 1.8 394 A A453.3 1.9 395 A A 429.3 1.9 396 A A 433.3 1.7 397 A A 375.36 2.21 1H NMR(300.0 MHz, DMSO) d 8.65 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H),8.20-8.19 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 4.78-4.74 (m, 1H), 3.41 (t,J = 5.4 Hz, 2H), 3.17 (MeOH), 2.89 (s, 3H), 2.50 (DMSO), 2.18- 2.15 (m,1H) and 1.99 (d, J = 7.4 Hz, 2H) ppm 398 A A 411 1.7 399 A 425 1.8 400 B439 1.9 401 B 437 1.9 402 B 453 2.1 403 B 465 2.1 404 D 439 2 405 B 4111.7 406 D 453 2.1 407 D 425 1.8 408 D 439 1.9 409 B 437 1.9 410 B 439 2411 A A 361.4 1.94 412 A A 376.4 3.53 413 D 361.3 2.41 414 A A 361.32.46 415 D 387 1.5 416 A A 361.3 1.56 417 A A 375.3 1.68 1H NMR (300.0MHz, DMSO) d 12.33 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.4Hz, 1H), 8.21 (t, J = 3.7 Hz, 2H), 8.02-7.98 (m, 1H), 7.21 (d, J = 5.8Hz, 1H), 4.86 (dd, J = 6.3, 10.5 Hz, 1H), 3.51-3.41 (m, 1H), 3.25-3.16(m, 1H), 2.13-1.85 (m, 4H), 1.66-1.52 (m, 1H) and 1.40- 1.20 (m, 1H) ppm418 A 421.37 1.79 1H NMR (300.0 MHz, DMSO) d 13.11 (d, J = 9.6 Hz, 1H),13.05 (s, H), 9.30 (s, 1H), 8.72 (d, 1H), 8.62 (d, 1H), 8.49 (s, 1H),8.18 (d, 1H), 6.83 (s, H), 6.72 (d, 1H), 4.30 (m, 1H), 3.88 (m, 1H),3.76(m, 1H) 3.46 (m, 1H), 3.10-3.01 (m, 4H), 2.12 (m, 1H), 1.92 (m, 1H),1.68-1.61 (m, 2H), 1.20 (t, 3H), and −0.00 (TMS) ppm 419 A A 449.39 2.081H NMR (300.0 MHz, DMSO) d 13.08 (s, 1H), 8.70 (d, 1H), 8.60 (d, 2H),8.48 (s, 1H), 8.18-8.12 (m, 1H), 6.64 (d, 1H), 5.91 (s, H), 4.30 (m,1H), 3.88 (m, 1H), 3.76(m, 1H) 3.46 (m, 1H), 3.10-3.01 (m, 4H), 2.08 (m,1H), 1.91 (m, 1H), 1.61 (dd, 4H), 1.47 (m, 2H), 0.86 (t, 3 H), and −0.00(TMS) 420 D 461 2.83 421 B 447 1.8 422 D 433 1.8 423 D 425 2 424 D 4471.8 425 A A 419.21 2.13 H NMR (300.0 MHz, DMSO) d 13.02 (s, 1H), 9.10(s, 2H), 8.67 (s, 1H), 8.44- 8.40 (m, 2H), 7.26 (d, J = 6.5 Hz, 1H),4.19 (s, 1H), 3.66 (d, J = 9.8 Hz, 1H), 3.48 (s, 3H), 2.13 (s, 1H), 2.02(d, J = 9.2 Hz, 1H), 1.78 (d, J = 9.6 Hz, 2H) and 1.47-1.34 (m, 4H) ppm426 A A 419.5 2.53 H NMR (300.0 MHz, DMSO) d 12.56 (s, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.35 (dd, J = 2.4, 6.8 Hz, 2H), 8.28 (d, J = 4.2 Hz, 1H),5.99 (d, J = 7.0 Hz, 1H), 5.80-5.63 (m, 1H), 3.91-3.87 (m, 1H),3.66-3.45 (m, 1H), 2.54 (s, 3H), 2.30 (d, J = 13.0 Hz, 1H), 2.04 (d, J =46.9 Hz, 1H), 1.78 (d, J = 8.5 Hz, 2H) and 1.56-1.23 (m, 4H) ppm 427 D432.4 2.69 H NMR (300.0 MHz, DMSO) d 12.59 (s, 1H), 8.72 (d, J = 2.3 Hz,1H), 8.41 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.29 (d, J =4.4 Hz, 1H), 8.23 (s, 1H), 6.19 (d, J = 7.8 Hz, 1H), 4.04- 3.97 (m, 1H),3.78-3.69 (m, 1H), 2.68 (s, 6H), 2.31 (d, J = 11.6 Hz, 1H), 1.95 (d, J =9.8 Hz, 1H), 1.79 (d, J = 10.4 Hz, 2H) and 1.60-1.32 (m, 4H) ppm 428 A A439.4 2.71 H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.72 (d, J = 2.3 Hz,1H), 8.38- 8.29 (m, 3H), 7.82 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.52(brs, 1H), 4.12- 4.05 (m, 1H), 2.92 (s, 3H), 2.09 (d, J = 12.8 Hz, 2H),1.78 (brs, 2H) and 1.49- 1.39 (m, 4H) ppm 429 B 403.4 2.57 430 A 418.52.57 H NMR (300.0 MHz, DMSO) d 12.61 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H),8.39- 8.31 (m, 4H), 6.12 (d, J = 6.7 Hz, 1H), 5.91-5.83 (m, 1H),4.29-4.13 (m, 1H), 4.02-3.91 (m, 1H), 2.55 (s, 3H), 1.93 (d, J = 12.8Hz, 1H) and 1.74-1.53 (m, 7H) ppm 431 A 432.4 2.77 H NMR (300.0 MHz,DMSO) d 12.54 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.33- 8.29 (m, 3H),7.96 (s, 1H), 5.72 (d, J = 6.9 Hz, 1H), 4.36 (s, 1H), 4.10 (s, 1H), 2.76(s, 6H), 1.96-1.87 (m, 2H), 1.74-1.63 (m, 4H) and 1.55-1.45 (m, 2H) ppm432 D 419.4 2.85 H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.67 (d, J =2.2 Hz, 1H), 8.35- 8.29 (m, 3H), 7.62 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H),4.50-4.40 (m, 1H), 4.20-4.10 (m, 1H), 3.46 (s, 3H), 1.87 (d, J = 10.9Hz, 2H), 1.71-1.65 (m, 4H) and 1.43 (d, J = 7.4 Hz, 2H) ppm 433 A A403.4 2.41 H NMR (300.0 MHz, DMSO) d 13.03 (s, 1H), 9.10 (s, 1H), 9.05(s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 8.43 (d, J= 2.3 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 4.15-4.07 (m, 1H), 3.93-3.87(m, 1H), 2.20-2.15 (m, 1H), 1.99-1.92 (m, 1H), 1.85- 1.79 (m, 2H), 1.74(s, 3H) and 1.52- 1.36 (m, 4H) ppm 434 A A 389.4 1.6 435 A A 403.4 1.8436 A 417.4 1.9 437 D 431.4 2 438 A A 418.4 1.7 439 A A 432.4 1.8 440 AA 405.4 1.8 441 B 419.4 1.9 442 B 433.4 2.1 443 A A 461.3 1.8 444 A A445.4 1.7 445 A 429.4 1.9 446 D 448.4 1.7 447 D 449.3 2 448 D 469.3 1.9449 B 419.4 1.7 450 B 431.4 1.7 451 B 415.4 1.8 452 A A 403.14 1.261975453 A A 419 1.178428 454 A A 439.11 1.548667 455 A A 418.16 1.690093 456A A 432.17 1.518183 457 A A 403.22 1.57 458 A A 418.16 0.76 459 A A432.17 1.46 460 A A 389.14 2.01 461 A A 389.14 2.05 462 B A 403.15 2.241H NMR (300.0 MHz, DMSO) d 12.35 (s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.27(d, J = 2.0 Hz, 1H), 8.21 (m, 2H), 7.28 (d, J = 6.0 Hz, 1H), 4.98 (dd, J= 6.9, 10.7 Hz, 1H), 3.88-3.79 (m, 1H), 3.84 (dd, J = 11.4, 15.5 Hz,1H), 3.49- 3.17 (m, 5H), 2.08 (d, J = 13.1 Hz, 1H), 1.95-1.88 (m, 3H),1.65-1.58 (m, 1H), 1.42 (m, 1H) and 1.04 (t, J = 7.0 Hz, 3H) ppm 463 D A475.2 2.26 DMSO d-6: 13.21 (s, 1H), 9.29 (d, 1H), 8.76 (d, 1H), 8.60 (s,1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.29 (m, 1H), 3.75 (m, 1H), 3.46 (m, 1H), 3.07-2.98 (m, 3H), 2.27-1.45 (m, 12H), 1.28-1.24 (m,2H), −0.00 (s, H) ppm 464 A A 435.14 2.03 DMSO d-6: 13.21 (s, 1H), 9.29(d, 1H), 8.76 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67(d, 1H), 4.29 (m, 1H), 3.75 (m, 1 H), 3.46 (m, 1H), 3.07-2.98 (m, 3H),2.2-2.1(m, 1H), 1.85-2.0(m, 1H), 1.72-1.57(m, 4H), 0.95(t, 3H) 465 B435.14 2 DMSO d-6: 13.21 (s, 1H), 9.29 (d, 1H), 8.76 (d, 1H), 8.60 (s,1H), 8.47 (s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.25(m, 1H), 3.79(m, 1H),3.53(m, 1H), 3.37(m, 1H), 3.17(m, 1H), 2.14(m, 1H), 1.90(m, 1H), 1.66-1.60(m, 1H), 1.21(d, 6H). 466 B 407.12 1.85 DMSO d-6: 13.21 (s, 1H),9.29 (d, 1H), 8.76 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.17 (d, 1H),6.67 (d, 1H), 4.4(m, 1H), 3.75(d, 1H), 3.4(m, 1H), 3.1(m, 1H), 2.9(s,H), 2.10-1.9(m, 2H), 1.8-1.65(m, 2H). 467 D 431.4 1.6 468 B 391.3 1.6469 D 465.3 2.3 470 D 479.3 2.3 471 A 375.3 1.6 472 B 405.3 1.6 473 B431.3 1.6 474 D 446.3 1.4 475 D 461.3 2.6 476 B 391.3 2.6 477 D 419.4 2478 B 431.3 1.6 479 D 479.3 2.3 480 A 375.3 1.6 481 B 405.3 2.2 482 A431.3 1.6 483 D 446.3 1.4 484 B 461.3 2.6 485 B 371.46 1.89 1H NMR(300.0 MHz, DMSO) d 13.09 (s, H), 9.3 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H),8.57 (d, 1H), 8.47 (s, 1H), 8.18-8.14 (m, 1H), 6.66-6.58 (m, 1H), 4.5(d,1H), 4.43-4.05 (m, 1H), 4.29 (s, H), 3.88 (d, 2H), 3.34- 3.08 (m, 2H),2.13 (s, 1H), 2.07 (s, 1H), 1.91 1.56 (m, 3H), 0.00 (TMS) 486 B 401.481.87 487 B 443.9 1.97 488 D 415.5 1.9 489 A 413.51 2.12 490 A A 385.431.7 1H NMR (300.0 MHz, DMSO) d 13.12 (s, 1H), 9.52 (s, 1H), 8.73 (d,1H), 8.65 (d, 1H), 8.45 (d, 1H), 8.14 (d, 1H), 6.63 (d, 1H), 4.29 (d, 1H), 4.04 (d, 1H), 3.80-3.32 (m, 3H), 3.10- 3.02 (m, 1H), 2.07 (s, 3H),1.99 (m, 2H), 1.8-1.6 (m, 2H), 1.55-1.24 (m, 2H) and −0.00 (TMS) ppm 491A 415.43 1.7 492 B 457.49 1.79 493 A A 429.46 1.74 494 B 427.52 1.92 495B 401.48 1.83 1H NMR (300.0 MHz, DMSO) d 13.12 (s, 1H), 9.44 (d, 1H),8.73 (d, 1H), 8.65 (d, 1H), 8.45 (d, 1H), 8.14 (d, J = 7.2 Hz, H), 6.80(d, 1H), 6.63 (d, 1H), 3.9(dd, 1H) 3.76 (dd, 1H), 3.60-3.50 (m, 3H),3.47 -(s, 3H), 3.05-2.8 (m, 2H), 1.93 (m, 2H), 1.83 (d, 2H), 1.42-1.35(m, 2H), and −0.00 (TMS) ppm 496 B 439.3 1.8 497 A A 403.3 1.7 498 A419.3 1.9 499 A A 432.5 1.8 500 A A 357.62 1.62 1H NMR (300.0 MHz, DMSO)d 13.02 (s, 1H), 8.73 (d, 1H), 8.66 (d, 1 H), 8.42 (d, 1H), 8.16 (d,1H), 8.06 (t, 1H), 6.83 (d, 1H), 5.05-4.99 (m, 1H), 3.52-3.42 (m, 1H),3.36 (d, H), 3.28- 3.24 (m, 1H), 2.50 (qn, J = 1.8 Hz, H), 2.00-1.80 (m,4H), 1.77-1.64 (m, 1H), 1.34 (m, 1H), 1.28 (s, H), 1.06 (t, J = 7.0 Hz,H) and 0.00 (TMS) ppm 501 B 341.38 1.56 1H NMR (300.0 MHz, DMSO) d 12.96(s, 1H), 8.66 (d, 1H), 8.46-8.41 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H),6.80 (d, 1H), 5.00 (dd, 1H), 3.54- 3.40 (m, 1H), 3.26-3.21 (m, 1H), 2.50(qn, J = 1.8 Hz, H), 2.03-1.86 (m, 4H), 1.64 (t, 1H), 1.36 (t, 1H) and−0.00 (TMS) ppm 502 A A 409.3 2.6 503 A 361.2 2.17 504 B A 403.3 2.85505 B 497.72 3.05 506 A A 418.5 2.09 1H NMR (300.0 MHz, DMSO) d 13.06(s, 1H), 9.24 (s, 1H), 9.05 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.3 Hz,1H), 8.52-8.45 (m, 2H), 4.35 (d, J = 8.0 Hz, 1H), 3.81 (qn, J = 6.1 Hz,1H), 3.59-3.39 (m, 2H), 3.18 (t, J = 11.6 Hz, 1H), 2.61 (d, J = 16 Hz,3H) and 2.12-1.67 (m, 6H) ppm 507 A A 390.42 1.69 508 D 397.37 1.59 509A A 404.45 1.67 510 D 343.39 0.65 511 D 343.42 1.29 512 D B 361.3 2.36513 B A 377.46 1.89 514 A A 418.78 1.26 1H NMR (300.0 MHz, MeOD) d 8.83(d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J= 4.1 Hz, 1H), 4.29-4.17 (m, 1H), 3.67- 3.60 (m, 1H), 3.60 (s, 3H), 2.37(m, 1H), 2.19 (m, 1H), 2.07-1.90 (m, 2H), 1.72-1.60 (m, 1H), 1.40-1.25(m, 2H) and −0.00 (TMS) ppm 515 D 463.5 2.47 1H NMR (300.0 MHz, CDCl3) d10.38 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.38(s, 1H), 8.08 (d, J = 3.4 Hz, 1H), 7.26 (s, CDCl3), 6.11 (d, J = 5.0 Hz,1H), 4.44 (d, J = 9.4 Hz, 1H), 4.02-3.62 (m, 6H), 3.55 (dd, J = 2.4,12.1 Hz, 1H), 3.35-3.27 (m, 1H) and 1.40-1.22 (m, 9H) ppm 516 B 419.41.91 517 B 448.54 2.26 1H NMR (300.0 MHz, DMSO) d 12.54 (s, 1H), 8.76(d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.26 (d, J= 3.9 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 4.28 (s, 1H),3.93-3.74 (m, 3H), 3.51-3.47 (m, 2H), 3.39-3.20 (m, 2H), 2.95 (dd, J =6.2, 13.1 Hz, 3H), 1.35-1.25 (m, 2H) and 0.76 (t, J = 7.3 Hz, 3H) ppm518 D 445.6 3.3 1H NMR (300.0 MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1H),8.53 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1H),4.75-4.73 (m, 1H), 3.74- 3.58 (m, 1H), 3.42 (m, 2H), 3.29- 3.22 (m, 2H),2.57 (m, 1H), 2.09- 2.03 (m, 1H), 1.96-1.76 (m, 4H), 1.06 (t, J = 7.1Hz, 3H) and 0.94 (t, J = 7.1 Hz, 3H) ppm 519 B 417.49 2.95 520 D 445.582.26 521 B 417.53 2.34 1H NMR (300.0 MHz, MeOD) d 8.93 (d, J = 2.4 Hz,1H), 8.22 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 7.99 (d, J = 4.0 Hz, 1H),4.53 (ddd, J = 7.1, 11.1 Hz, 1H), 3.15-3.02 (m, 2H), 2.43-2.34 (m, 1H),2.30-2.26 (m, 1H), 1.97- 1.82 (m, 3H), 1.77-1.65 (m, 2H), 1.47-1.35 (m,2H) and 0.97 (t, J = 7.3 Hz, 3H) ppm 522 D 375.46 1.68 523 D 389.54 1.721H NMR (300.0 MHz, MeOD) d 8.65 (d, J = 2.3 Hz, 1H), 8.54 (s, 1H), 8.43(d, J = 5.1 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 4.82-4.72 (m, 1H), 3.66-3.53 (m, 1H), 2.96 (s, 3H), 2.77 (s, 3H), 2.33 (d, J = 12.3 Hz, 2H),2.10- 1.97 (m, 2H) and 1.75-1.48 (m, 4H) ppm 524 A A 362.48 1.95 525 A A421.52 1.48 1H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.72 (d, J = 2.4Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.17 (d, J= 4.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 4.54 (m, 1H), 4.44 (s, 1H),4.36 (m, 1H), 3.64 (s, 1H), 3.40 (m, 1H), 3.03 (t, J = 11.0 Hz, 1H),2.77 (m, 1H), 2.47-2.25 (m, 2H), 2.22-2.12 (m, 2H), 1.99-1.90 (m, 1H),1.70-1.60 (m, 2H) and 1.45 (m, 1H) ppm 526 B A 421 2.36 527 D D 435.12.49 528 B D 447.1 2.64 529 B D 433.1 2.45 530 D B 447.1 1.93 531 B A445.1 2.56 532 B A 441 2.4 533 B A 467 2.4 534 B A 406 1.96 535 B D434.1 2.17 536 B D 448.1 2.34 537 A A 435.54 1.56 1H NMR (300.0 MHz,DMSO) d 12.35 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz,1H), 8.19-8.09 (m, 2H), 7.36 (d, J = 7.5 Hz, 1H), 4.53 (dd, J = 4.5, 8.0Hz, 1H), 4.27 (s, 1H), 3.77-3.72 (m, 1H), 3.36-3.20 (m, 3H), 3.22 (s,3H), 3.03-2.97 (m, 1H), 2.76 (d, J = 10.6 Hz, 1H), 2.44-2.14 (m, 2H),2.08 (m, 2H), 1.99-1.94 (m, 1H), 1.71-1.63 (m, 2H), 1.44 (m, 1H) and1.23-1.15 (m, 1H) ppm 538 A A 419.55 1.61 1H NMR (300.0 MHz, DMSO) d12.53 (s, 1H), 10.32 (s, 1H), 8.69 (dd, J = 2.5, 5.2 Hz, 1H), 8.56 (d, J= 2.4 Hz, 1H), 8.31 (m, 2H), 7.97 (s, 1H), 4.76 (m, 1H), 3.92 (m, 2H),3.84- 3.55 (m, 2H), 3.40-2.80 (m, 3H), 2.14-1.90 (m, 3H), 1.80-1.74 (m,2H), 1.65 (m, 1H), 1.43-1.23 (m, 2H) and 0.96-0.85 (m, 3H) ppm 539 B A403.44 2.13 540 A A 361.5 1.43 541 A A 390.46 2.43 542 B B 361.37 1.42543 A A 417.44 2.52 544 D A 389.42 1.94 545 A 376.46 375.13 1H NMR(300.0 MHz, DMSO) d 12.32 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.92 (d, J = 8.2 Hz, 1H),4.56 (s, 1H), 4.31 (dd, J = 5.9, 8.6 Hz, 1H), 1.89-1.35 (m, 8H), 1.17(s, 3H) and 0.00 (TMS) ppm 546 A 419.49 418.17 1H NMR (300.0 MHz, CDCl3)d 9.60 (s, H), 8.87 (d, J = 2.3 Hz, H), 8.33 (d, J = 2.3 Hz, H), 8.17(d, J = 2.7 Hz, H), 8.09 (d, J = 3.3 Hz, H), 8.04 (s, H), 7.28 (s, H),5.34 (d, J = 11.5 Hz, H), 4.45-4.42 (m, H), 3.09 (d, J = 11.3 Hz, H),2.98 (s, H), 2.90 (d, J = 0.5 Hz, H), 2.72 (d, J = 12.9 Hz, H), 2.62 (d,J = 6.3 Hz, H), 2.40 (s, H), 1.94 (d, J = 11.6 Hz, H), 1.86-1.72 (m, H),1.62 (s, H), 1.27 (s, H) and 1.22 (s, H) ppm 547 A 403.22 3.99 1H NMR(300 MHz, MeOD) d 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, J =4.1, 1H), 4.23 (t, J = 11.4, 1H), 3.90 (t, J = 11.4, 1H), 2.35 (d, J =11.6, 1H), 2.20 (d, J = 12.5, 1H), 2.00 (d, J = 15.9, 2H), 1.92 (s, 3H),1.67 (dd, J = 26.3, 13.2, 1H), 1.53-1.06 (m, 3H) ppm LCMS 548 A 419.462.82 549 A 432.5 2.6 550 A 449.48 448.18 1H NMR (300.0 MHz, DMSO) d12.33 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H),8.22-8.20 (m, 2H), 6.72-6.62 (m, 1H), 4.61 (dd, J = 4.2, 10.0 Hz, 1H),4.54 (m, 1H), 3.75-3.71 (m, 1H), 3.34-3.22 (m, 1H), 3.22 (d, 3H),2.88-2.42 (m, 4H), 2.41-2.25 (m, 4H), 1.93 (m, 1H), 1.56 (m, 2H), 0.90(d, J = 6.7 Hz, 3H) and −0.00 (TMS) ppm 551 A 463.51 462.19 1H NMR(300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.19-8.16 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 4.42- 4.37(m, 2H), 3.70 (s, 1H), 3.52- 3.42 (m, 1H), 3.35-3.25 (m, 1H), 2.99 (m,1H), 2.73 (m, 1H), 2.43- 2.11 (m, 4H), 1.94 (m, 1H), 1.75- 1.60 (m, 2H),1.52-1.40 (M, 1H), 1.10-0.99 (m, 6H) and 0.00 (TMS) ppm 552 A 376.232.22 CD3OD: 8.7(d, 1H), 8.45(s, 1H), 8.35(d, 1H), 8.25(d, 1H), 4.37(t,1H), 3.58-3.48(m, 1H), 3.4(s, 3H), 2.55(dd, 1H), 2.23-2.1(m, 2H),2.05-1.95(m, 1H), 1.7-1.4(m, 3H), 1.35-1.25(m, 1H), 0.00(TMS) 553 A A390.35 2.05 1H NMR (300.0 MHz, MeOD) d 8.89 (d, J = 2.4 Hz, 1H), 8.44(s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.75 (m,1H), 2.75-2.66 (m, 1H), 2.25-2.16 (m, 2H), 1.99-1.89 (m, 2H), 1.71-1.29(m, 4H) and 1.37 (m, contaminant) ppm 554 C B 390.41 2.3 1H NMR (300.0MHz, MeOD) d 8.89 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 2.4Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 2.75-2.66 (m, 1H),2.24-2.17 (m, 2H), 1.94-1.89 (m, 2H) and 1.74-1.36 (m, 4H) ppm 555 C A375 1.93 1H NMR (300.0 MHz, MeOD) d 8.75 (d, J = 2.4 Hz, 1H), 8.31 (d, J= 2.4 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 3.96 (dd, J =5.8, 14.4 Hz, 1H), 3.73 (dd, J = 4.3, 14.3 Hz, 1H), 3.08-3.00 (m, 1H),2.05-1.87 (m, 3H), 1.80 (m, 3H) and 1.48-1.39 (m, 4H) ppm 556 C A 446.82.8 1H NMR (300.0 MHz, MeOD) d 8.74 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H),8.38 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 3.85-3.81 (m, 2H),3.75 (d, J = 8.5 Hz, 2H), 3.26 (s, 3H), 1.97- 1.77 (m, 5H) and 1.43-1.35(m, 4H) ppm 557 A 452.6 2.8 1H NMR (300.0 MHz, MeOD) d 8.78 (d, J = 2.4Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.26 (d, J= 5.4 Hz, 1H), 4.12 (dd, J = 4.5, 13.7 Hz, 1H), 3.89 (dd, J = 7.1, 13.8Hz, 1H), 3.26-3.16 (m, 1H), 3.00 (s, 3H), 2.18-1.90 (m, 2H), 1.79-1.74(m, 2H) and 1.50-1.25 (m, 4H) ppm 558 A A 376.2 2.49 1H NMR (300.0 MHz,MeOD) d 8.78 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.33 (d, J = 2.2 Hz,1H), 8.25 (d, J = 5.2 Hz, 1H), 4.98 (dd, J = 7.2 Hz, 1H), 2.27-2.03 (m,5H) and 1.86-1.76 (m, 1H) ppm 559 A A 389.8 2.27 1H NMR (300.0 MHz,MeOD) d 8.75 (d, J = 2.4 Hz, 1H), 8.38-8.35 (m, 2H), 8.24 (d, J = 5.1Hz, 1H), 4.70- 4.62 (m, 1H), 3.25-3.17 (m, 1H), 2.32 (m, 1H), 2.14-1.80(m, 4H) and 1.68-1.54 (m, 3H) ppm 560 C D 418.46 3.21 H NMR (300.0 MHz,MeOD) d 8.95 (s, 1H), 8.23-8.14 (m, 2H), 8.00 (m, 1H), 4.61 (m, 1H),3.96-3.92 (m, 2H), 2.61 (m, 1H), 2.14-2.04 (m, 2H), 1.89-1.35 (m, 7H)and 1.04- 0.99 (m, 3H) ppm 561 B A 418.41 2.73 H NMR (300.0 MHz, MeOD) d8.95 (s, 1H), 8.19 (m, 2H), 7.99 (s, 1H), 4.61 (m, 1H), 3.93 (m, 2H),2.61 (m, 1H), 2.17-2.05 (m, 2H), 1.89-1.32 (m, 7H) and 1.00 (m, 3H) ppm562 C A 376.43 8.62 H NMR (300.0 MHz, DMSO) d 8.85 (enantiomer 1) (d, J= 2.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 4.2Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.52 (s, 1H), 4.32-4.25 (m, 1H),1.90- 1.33 (m, 8H) and 1.15 (s, 3H) ppm 563 A A 376.43 11.16 H NMR(300.0 MHz, DMSO) d 12.31 (enantiomer 2) (s, 1H), 8.86 (d, J = 2.4 Hz,1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 (d, J =4.2 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 4.54 (s, 1H), 4.30 (t, J = 8.8Hz, 1H), 1.86-1.25 (m, 8H) and 1.16 (s, 3H) ppm 564 C A 445.7 1.91 565 BA 376.39 2.43 H NMR (300.0 MHz, DMSO) d 12.48 (s, 1H), 8.71 (d, J = 2.3Hz, 1H), 8.35- 8.31 (m, 2H), 8.26 (d, J = 4.3 Hz, 2H), 8.02 (s, 1H),4.57-4.44 (m, 1H), 2.87 (qn, J = 8.3 Hz, 1H), 2.39-2.32 (m, 1H),2.15-2.05 (m, 1H), 2.00- 1.86 (m, 3H) and 1.82-1.70 (m, 1H) ppm 566 A A376.4 2.34 H NMR (300.0 MHz, DMSO) d 12.42 (s, 1H), 8.72 (d, J = 2.2 Hz,1H), 8.29 (m, 2H), 8.22 (d, J = 4.1 Hz, 1H), 7.87 (s, 1H), 4.56-4.49 (m,1H), 2.87 (dd, J = 8.4, 25.0 Hz, 1H), 2.87 (s, 1H), 2.42-2.33 (m, 1H),2.15-2.04 (m, 1H), 2.00-1.85 (m, 3H) and 1.81- 1.70 (m, 1H) ppm 567 A A404.42 2.13 H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H), 8.72 (d, J = 2.4Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.17 (d, J = 4.0 Hz,1H), 7.41 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 4.35-4.29 (m,1H), 2.98-2.75 (m, 1H), 2.92 (d, J = 6.8 Hz, 2H), 2.68 (d, J = 10.8 Hz,1H), 2.29-2.19 (m, 2H), 1.96-1.92 (m, 1H), 1.80-1.65 (m, 2H) and1.53-1.42 (m, 1H) ppm 568 C D 432.46 3.08 H NMR (300.0 MHz, DMSO) d 8.80(d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J= 4.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 4.72 (qn, J = 6.2 Hz, 1H),4.55-4.48 (m, 1H), 2.61-2.54 (m, 1H), 1.96 (m, 2H), 1.77 (m, 2H),1.63-1.41 (m, 3H), 1.30-1.23 (m, 1H) and 0.93 (d, J = 6.2 Hz, 6H) ppm569 C D 432.48 2.69 H NMR (300.0 MHz, DMSO) d 12.57 (s, 1H), 8.80 (d, J= 2.4 Hz, 1H), 8.36- 8.28 (m, 4H), 4.75 (td, J = 12.5, 6.2 Hz, 1H), 4.52(m, 1H), 2.65-2.56 (m, 1H), 2.00 (m, 2H), 1.83-1.76 (m, 2H), 1.57-1.42(m, 3H), 1.32-1.24 (m, 1H) and 0.94 (d, J = 6.2 Hz, 6H) ppm 570 A A419.42 2 H NMR (300.0 MHz, MeOD) d 8.81 (d, J = 2.1 Hz, 1H), 8.20 (d, J= 2.3 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J = 4.1 Hz, 1H), 4.26-4.18 (m,1H), 3.71- 3.52 (m, 1H), 3.59 (s, 3H), 2.36 (d, J = 10.5 Hz, 1H), 2.18(d, J = 10.7 Hz, 1H), 2.04-1.86 (m, 2H), 1.57 (s, 1H) and 1.43-1.15 (m,3H) ppm 571 A A 376.41 1.97 CD3OD: 8.69(d, 1H), 8.55(s, 1H),(diastereomer 1) 8.38(d, 1H), 8.33(d, 1H), 4.62(m, 1H), 2.0-1.6(m, 8H),1.35(s, 3H) 572 A A 376.42 2.39 CD3OD: 8.78(d, 1H), 8.55(s, 1H),(diasteroemer 2) 8.35(s, 1H), 8.25(d, 1H), 4.8(m, 1H), 2.25-1.95(m 2H),1.80-1.60(m, 4H), 1.45-1.3(m, 2H), 1.3(s, 3H) 573 A 419.42 1.87 H NMR(300.0 MHz, DMSO) d 12.51 (s, 1H), 10.28-10.00 (m, 1H), 8.70 (s, 1H),8.38 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 4.2 Hz, 1H), 7.89-7.75 (m, 1H), 4.70-4.50 (m, 1H), 4.33-4.29 (m, 1H), 3.79-3.45 (m, 2H),3.20-2.80 (m, 2H), 2.12-1.95 (m, 3H), 1.72-1.60 (m, 1H) and 1.52 (d, J =5.5 Hz, 3H) ppm 574 A 448.41 2.99 1H NMR (300.0 MHz, DMSO) d 8.74 (d, J= 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 4.0Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 4.42 (m, 1H), 4.02-3.86 (m, 2H),3.35- 3.23 (m, 2H), 3.08 (s, 3H), 2.69-2.60 (m, 1H), 1.99 (m, 2H), 1.77(m, 2H), 1.62-1.40 (m, 3H) and 1.27 (m, 1H) ppm 575 A 404.38 3.12 1H NMR(300.0 MHz, DMSO) d 8.76 (d, J = 2.5 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H),8.19 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 4.47-4.37 (m, 1H), 3.40 (s, 3H), 2.68- 2.59 (m, 1H), 2.05-1.97 (m, 2H),1.84-1.75 (m, 2H), 1.63-1.40 (m, 3H) and 1.31-1.23 (m, 1H) ppm 576 A403.4 1.78 1H NMR (300 MHz, MeOD) d 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s,1H), 7.99 (d, J = 4.1, 1H), 4.23 (t, J = 11.4, 1H), 3.90 (t, J = 11.4,1H), 2.35 (d, J = 11.6, 1H), 2.20 (d, J = 12.5, 1H), 2.00 (d, J = 15.9,2H), 1.92 (s, 3H), 1.67 (dd, J = 26.3, 13.2, 1H), 1.53-1.06 (m, 3H). 577A 405.4 1.95 1H NMR (300.0 MHz, DMSO) d 12.46 (s, 1H), 8.70 (d, J = 2.4Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.29 (d, J= 3.9 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 4.70-4.50 (m, 1H), 4.21 (s,2H), 3.80-3.70 (m, 1H), 3.55-3.47 (m, 1H), 3.20-2.90 (m, 2H), 2.10-1.95(m, 3H) and 1.69- 1.60 (m, 1H) ppm 578 A A 390.41 2.82 1H NMR (300.0MHz, DMSO) d 12.51 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.3Hz, 2H), 8.29 (d, J = 4.3 Hz, 1H), 7.55 (s, 1H), 4.53 (s, 1H), 3.05 (m,1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.79 (m, 3H) and 1.51 (m, 3H) ppm 579 A390.36 2.92 1H NMR (300.0 MHz, DMSO) d 12.52 (s, 1H), 8.68 (d, J = 2.3Hz, 1H), 8.33 (d, J = 2.5 Hz, 2H), 8.30 (d, J = 4.4 Hz, 1H), 7.57 (s,1H), 4.53 (m, 1H), 3.05 (m, 1H), 2.15-2.07 (m, 1H), 1.96 (m, 1H),1.81-1.76 (m, 3H) and 1.51 (m, 3H) ppm 580 A 376.44 2.28 1H NMR (300.0MHz, MeOD) d 8.88 (d, 1 H), 8.45 (s, 1H), 8.39 (d, J1H), 8.26 (d, H),4.53 (t, 1H), 3.95-3.88 (m, 1H), 2.03-1.81 (m, 7H), 1.69 (m, 1H),0.0(TMS), 581 A 390.42 3 1H NMR (300.0 MHz, MeOD) d 8.80 (d, 1H), 8.54(s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 4.43 (d, 1H), 2.17-1.75 (m, 8H),1.74 (m, 2H), 1.65 (s, 3H), 0.00(TMS) 582 A 404.43 3.21 1H NMR (300.0MHz, DMSO) d 12.46 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.32-8.28 (m, 3H),7.10 (d, J = 7.1 Hz, 1H), 4.27-4.20 (m, 1H), 2.26 (d, J = 10.1 Hz, 1H),1.93 (m, 1H), 1.83 (m, 1H), 1.68-1.59 (m, 3H), 1.36 (m, 2H) and 1.24 (s,3H) ppm 583 A 418.45 1.65 1H NMR (300.0 MHz, MeOD) d 8.72 (d, 1H), 8.6(d, 1H), 8.3(m, 2H), 4.1(m, 1H), 3.9-3.8 (m, 1H), 3.75- 3.50(dd, 1H),2.45-2.35(m, 1H), 2.35- 2.15(m, 2H), 1.95-1.85(m 1H), (1.65(dd, 3H),0.00(TMS) ppm 584 A 483.44 2.52 1H NMR (300.0 MHz, DMSO) d 12.45 (m,1H), 8.71 (d, J = 8.5 Hz, 1H), 8.31 (m, 2H), 8.01 (m, 1H), 5.33 (s, 1H),4.62-4.43 (m, 2H), 4.39- 3.72 (m, 5H), 3.68 (s, 2H), 3.43-3.40 (m, 1H),3.15 (s, 1H), 3.07 (s, 1H), 2.33 (s, 2H) and 2.08 (s, 2H) ppm 585 A418.41 3.21 1H NMR (300 MHz, MeOD) ? 8.80 ? 8.76 (m, 1H), 8.37 (s, 1H),8.35 (d, J = 2.3, 1H), 8.27 ? 8.23 (m, 1H), 4.49 ? 4.42 (m, 1H), 2.43 ?2.34 (m, 1H), 2.09 (d, J = 6.2, 1H), 1.98 ? 1.36 (m, 12H), 0.94 (dd, J =11.3, 3.8, 3H). 586 A A 418.38 2.95 1H NMR (300 MHz, MeOD) ? 8.93 ? 8.85(m, 2H), 8.93 ? 8.87 (m, 1H), 8.31 (dd, J = 4.5, 1.2, 2H), 8.31 (dd, J =4.5, 1.2, 2H), 8.30 (d, J = 2.3, 1H), 8.19 (d, J = 5.0, 1H), 5.26 ? 5.20(m, 1H), 3.37 (dd, J = 3.3, 1.6, 2H), 3.33 (ddt, J = 6.6, 3.3, 1.6,118H), 2.11 (dd, J = 8.0, 5.8, 2H), 1.80 (tdd, J = 21.2, 18.9, 11.6,8H), 1.63 ? 1.54 (m, 3H), 0.86 (q, J = 7.4, 4H) 587 A A 421.4 1.56 588 AA 421.4 1.56 589 A 427.42 1.56 H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H),11.99 (m, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.16(d, J = 4.0 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H),6.93 (s, 2H), 4.31 (s, 1H), 4.19 (m, 1H), 3.66 (d, J = 14.0 Hz, 1H),3.55 (d, J = 14.0 Hz, 1H), 3.01 (m, 1H), 2.77 (m, 1H), 2.15-1.90 (m,3H), 1.75-1.68 (m, 1H) and 1.49-1.37 (m, 1H) ppm 590 C 433.37 2.09 H NMR(300.0 MHz, MeOD) d 8.81 (d, 1H), 8.19 (d, 2H), 7.98 (d, 1H), 4.48 (s,1H), 2.92-2.86 (m, 1H), 2.80- 2.56(m, 3 H), 1.94-1.83 (m, 3H), 1.72-1.65(m, 1H), 1.25(d, 6H), 0.00 (s, H) ppm 591 A A 433.41 2.6 H NMR (300.0MHz, MeOD) d 8.82 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.16(s, 1H), 7.99 (d, J = 4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04- 3.96 (m,1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, J = 11.6 Hz, 1H), 2.21 (d, J =12.5 Hz, 1H), 2.02-1.93 (m, 2H), 1.74-1.62 (m, 1H) and 1.54- 1.28 (m,3H) ppm 592 A 463.42 2.52 1H NMR (300 MHz, METHANOL- d4) Shift 8.84 (s,1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 3.97 Hz, 1H), 4.18-4.34(m, 1H), 4.14 (br. s., 2H), 3.49-3.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, J =9.06 Hz, 1H), 2.19 (d, J = 13.41 Hz, 1H), 1.84-2.11 (m, 2H), 1.51- 1.78(m, 1H), 1.12-1.47 (m, 3H) 593 A 418.21 1.47 H NMR (300.0 MHz, MeOD) d8.85 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.99(d, J = 4.1 Hz, 1H), 4.28-4.20 (m, 1H), 2.82- 2.73 (m, 1H), 2.65 (s,2H), 2.40 (d, J = 10.2 Hz, 1H), 2.15 (d, J = 8.5 Hz, 1H), 2.05-1.92 (m,2H), 1.64-1.55 (m, 1H) and 1.44-1.12 (m, 3H) ppm 594 A A 427.37 1.61 HNMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 11.86-11.77 (m, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 3.9 Hz, 1H), 8.10(d, J = 2.5 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.87 (s,1H), 4.19 (m, 1H), 3.57 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H),3.04 (d, J = 8.3 Hz, 1H), 2.80 (d, J = 10.4 Hz, 1H), 2.10-1.90 (m, 3H),1.72-1.62 (m, 2H) and 1.51-1.35 (m, 1H) ppm 595 A A 405.37 1.65 H NMR(300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.18-8.15 (m, 2H), 7.32 (d, J = 7.1 Hz, 1H), 4.20 (d, J =7.1 Hz, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.19 (s, 3H), 3.10-3.06 (m, 1H),2.82-2.78 (m, 1H), 2.57-2.50 (m, 2H), 2.11-1.95 (m, 3H), 1.71-1.63 (m,2H) and 1.48-1.35 (m, 1H) ppm 596 A A 402.34 2.99 H NMR (300.0 MHz,MeOD) d 8.86 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 2.3 Hz,1H), 8.25 (d, J = 5.1 Hz, 1H), 4.59 (d, J = 8.1 Hz, 1H), 3.00 (d, J =8.0 Hz, 1H), 2.62 (m, 1H), 2.55 (m, 1H), 2.11 (d, J = 10.4 Hz, 1H),1.85-1.59 (m, 3H) and 1.51-1.36 (m, 2H) ppm 597 C A H NMR (300.0 MHz,MeOD) d 8.78 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 8.34 (d, J = 2.3 Hz,1H), 8.23 (d, J = 4.9 Hz, 1H), 4.71-4.67 (m, 1H), 3.25- 3.22 (m, 1H),2.94 (m, 1H), 2.77 (m, 1H), 1.86 (d, J = 11.0 Hz, 1H) and 1.70-1.58 (m,5H) ppm 598 A A 432.41 1.83 H NMR (300.0 MHz, MeOD) d 8.86 (d, J = 2.4Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.02-7.97 (m, 1H), 4.45(m, 1H), 3.14 (d, J = 10.8 Hz, 1H), 2.75 (d, J = 10.3 Hz, 1H), 2.38-2.26(m, 2H), 2.12-2.08 (m, 1H), 1.92-1.70 (m, 2H), 1.66-1.55 (m, 1H), 1.20(d, J = 7.5 Hz, 6H), 0.00 (TMS) ppm 599 A A 446.46 2.28 H NMR (300.0MHz, MeOD) d 8.86 (d, J = 2.4 Hz, H), 8.23 (d, J = 2.3 Hz, H), 8.17 (s,H), 8.03 (d, J = 4.1 Hz, H), 4.46 (m, 1H), 3.05 (d, J = 12.8 Hz, 1H),2.66 (s, 3H), 2.34 (dd, J = 11.3, 20.6 Hz, 2H), 2.08 (d, J = 12.3 Hz,1H), 1.89-1.71 (m, 2H), 1.66-1.54 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H), and−0.00 (TMS) ppm 600 A A 460.46 2.31 H NMR (300.0 MHz, MeOD) d 8.81 (d, J= 2.4 Hz, H), 8.22 (d, J = 2.4 Hz, H), 8.14 (s, H), 8.02 (d, J = 4.0 Hz,H), 4.45-4.37 (m, 1H), 3.61 (s, H), 2.97 (d, J = 8.8 Hz, 1H), 2.80 (s,3H), 2.80- 2.75(m, 1H), 2.39-2.32 (m, 2H), 2.32 (s, H), 2.15 (dd, J =3.6, 12.7 Hz, 1H), 1.91-1.79 (m, 2H), 1.53-1.47 (m, 1H), 1.10 (d, J =6.8 Hz, 6H), and −0.00 (TMS) ppm 601 A A 490.47 2 H NMR (300.0 MHz,MeOD) 8.88 (d, J = 2.3 Hz, H), 8.23 (d, J = 2.3 Hz, H), 8.17 (s, H),8.02 (d, J = 4.1 Hz, H), 4.47-4.41 (m, 1H), 3.38 (m, H), 3.32- 3.23 (m,4H), 3.24(s, 3H), 3.12- 3.07 (m, 1H), 2.73 (d, J = 10.8 Hz, 1H),2.35-2.29 (m, 2H), 2.19-2.15 (m, 1H), 1.91-1.80 (m, 2H), 1.47- 1.42 (m,1H), 1.10 (d, J = 6.5 Hz, 6H), and −0.00 (s, H) ppm 602 A A 472.42 2.31H NMR (300.0 MHz, MeOD) d 8.82 (d, J = 2.4 Hz, H), 8.22 (d, J = 2.3 Hz,H), 8.15 (s, H), 8.01 (d, J = 4.0 Hz, H), 4.41(m, 1H), 3.02 (d, J = 10.0Hz, 1H), 2.59-2.47 (m, 2H), 2.40-2.30 (m, 2H), 2.09-2.01 (m, 1H), 1.89-1.85 (m, 1H), 1.78-1.66 (m, 1H), 1.61-1.55 (m, 1H), 1.10 (d, J = 6.6 Hz,6H), 0.68-0.63 (m, 2H), 00.44- 0.40 (m, 2H) and 0.00 (s, H) ppm 603 A A434.2 1.54 H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.71 (d, J = 1.6 Hz,1H), 8.28 (d, J = 1.5 Hz, 1H), 8.20-8.16 (m, 2H), 7.32 (s, 1H),7.19-7.11 (m, 1H), 5.20 (s, 1H), 4.24 (s, 1H), 3.99 (s, 1H), 3.01 (d, J= 9.0 Hz, 1H), 2.70-2.64 (m, 2H), 2.36-2.27 (m, 3H), 1.94 (s, 1H), 1.71(s, 2H) and 1.48 (s, 1H) ppm 604 A A 461.2 1.79 H NMR (300.0 MHz, DMSO)d 8.68 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19-8.14 (m, 2H),7.33 (d, J = 7.5 Hz, 1H), 4.21 (t, J = 5.9 Hz, 2H), 4.00-3.96 (m, 1H),3.54 (t, J = 7.6 Hz, 1H), 3.15 (d, J = 8.9 Hz, 1H), 3.03-2.91 (m, 1H),2.78 (d, J = 10.5 Hz, 1H), 2.11-1.92 (m, 3H), 1.71 (s, 2H), 1.43-1.35(m, 1H), 1.27 (s, 3H), 1.22 (s, 1H) and 1.14 (s, 3H) ppm 605 C C 391.071.425 H NMR (300.0 MHz, DMSO) d 12.51 (s, 1H), 8.72-8.57 (m, 3H), 8.35-8.32 (m, 3H), 7.94 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.11(d, J = 7.9 Hz, 1H), 5.02 (m, 1H), 3.69 (m, 1H), 3.33-3.24 (m, 4H), 2.29(s, 1H) and 2.12-2.06 (m, 2H) ppm 606 A A 432.15 1.62 607 C C 433.181.87 H NMR (300.0 MHz, DMSO) d 12.48 (s, 1H), 8.68 (s, 1H), 8.32-8.29(m, 3H), 7.68 (d, J = 2.5 Hz, 1H), 4.77- 4.73 (m, 1H), 4.27-4.10 (m,2H), 3.76-3.40 (m, 2H), 3.19-3.04 (m, 2H) and 2.15-1.83 (m, 6H) ppm.2.05 and 2.03 (acetyl rotamers, two burried s, 3H) 608 A A 433.36 2.88 HNMR (300.0 MHz, DMSO) d 9.03 (s, 1H), 8.65 (s, 1H), 8.48 (d, J = 5.1 Hz,1H), 8.41 (s, 1H), 4.64 (s, 1H), 4.27 (s, 1H), 2.97 (m, 2H), 2.30 (d, J= 10.5 Hz, 1H), 2.06 (s, 2H), 1.91 (d, J = 11.2 Hz, 2H), 1.64-1.23 (m,5H), 0.99 (t, J = 6.9 Hz, 3H), and 0.00 (TMS), ppm 609 A A 433.32 2.79 HNMR (300.0 MHz, MeOD) d 8.68(s, 1H), 8.64 (s, 1 H), 8.37 (d, J = 1.8 Hz,1H), 8.29 (d, J = 5.4 Hz, 1H), 5.15 (s, 1H), , 4.71-4.63 (m, 1H), 3.33(d, J = 11.6 Hz, 1H), 3.10 (m, 2H), 2.26 (m, 2H), 2.04 (m, 3H), 1.83 (m,1H), 1.70-1.50 (m, 2H), 1.03 (m, 3H), and 0.00 (TMS) ppm 610 A C 449.421.52 H NMR (300.0 MHz, MeOD) d 8.85 (d, J = 2.3 Hz, 1H), 8.22 (d, J =2.2 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J = 4.1 Hz, 1H), 4.20 (m, 1H), 3.82(dd, J = 3.9, 8.2 Hz, 1H), 3.55-3.45 (m, 1H), 3.30 (s, 3H), 3.23-3.07(m, 1H), 2.86- 2.77 (m, 2H), 2.68-2.59 (m, 1H), 2.44 (d, J = 10.9 Hz,1H), 2.15 (d, J = 9.8 Hz, 1H), 2.07-1.94 (m, 2H), 1.65- 1.56 (m, 1H) and1.42-1.17 (m, 3H) ppm 611 A A 447.4 1.95 H NMR (300.0 MHz, MeOD) d 8.78(d, J = 2.3 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J= 4.0 Hz, 1H), 4.25-4.18 (m, 1H), 3.96- 3.88 (m, 1H), 3.61 (t, J = 6.2Hz, 2H), 3.31 (s, 3H), 2.39 (t, J = 6.2 Hz, 2H), 2.37 (d, J = 17.1 Hz,1H), 2.18 (d, J = 12.0 Hz, 1H), 2.03-1.91 (m, 2H), 1.67 (q, J = 13.4 Hz,1H) and 1.45- 1.22 (m, 3H) ppm 612 A A 418.37 4.59 H NMR (300.0 MHz,MeOD) d 8.77 (s, 1H), 8.37 (d, J = 2.7 Hz, 2H), 8.26 (d, J = 4.7 Hz,1H), 4.46 (m, 1H), 2.39 (m, 1H), 2.10 (m, 1H), 1.92-1.35 (m, 8H) and0.93 (t, J = 7.7 Hz, 3H) ppm 613 A A 388.13 1.82 614 A A 459.35 3.06 HNMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.18(s, 2H), 7.31 (d, J = 6.2 Hz, 1H), 6.10 (d, J = 5.3 Hz, 1H), 4.16 (s,2H), 3.04 (s, 1H), 2.79 (d, J = 8.6 Hz, 1H), 2.59 (d, J = 9.9 Hz, 2H),2.26 (t, J = 9.5 Hz, 2H), 1.94 (s, 1H), 1.72 (s, 2H) and 1.48 (s, 1H)ppm 615 A A 378.3 3.59 616 C C 378.3 3.74 617 A A 386.35 3.58 H NMR(300.0 MHz, DMSO) d 13.15 (diasteromer 1) (s, H), 9.58 (s, 1H), 9.49 (d,J = 6.4 Hz, 111H), 9.23 (s, H), 8.59 (s, H), 8.52 (d, J = 5.0 Hz, 1H),8.42 (s, 1H), 4.52 (s, 1H), 3.34 (s, 1H), 3.17 (s, 1H), 2.11 (s, 2H),1.96-1.85 (m, 4H), 1.5- 1.2 (m, 2H), and −0.00 (s, H) ppm 618 A A 386.343.16 H NMR (300.0 MHz, DMSO) d 13.13 (diasteromer 2) (s, 1H), 9.45 (s,1H), 9.28 (s, 1H), 8.66 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.42 (s, 1H),4.61 (s, 1H), 3.33 (s, 1H), 3.17 (s, 1H), 2.16 (d, J = 12.5 Hz, H), 2.06(s, 1H), 2.02-1.78 (m, 4H), 1.66-1.60 (m, 2H), 1.46 (m, 1H), and 0.00(s, H) ppm 619 A A 446.23 2.23 H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H),8.71 (s, 1H), 8.28 (s, 1H), 8.17 (d, J = 6.9 Hz, 2H), 7.42 (s, 1H), 7.35(d, J = 7.6 Hz, 1H), 4.73 (d, J = 7.4 Hz, 1H), 4.23 (s, 1H), 3.51 (d, J= 5.8 Hz, 1H), 3.17 (dd, J = 9.2, 17.9 Hz, 1H), 3.04 (d, J = 10.9 Hz,2H), 2.89 (s, 1H), 2.63 (d, J = 5.6 Hz, 1H), 2.25 (d, J = 11.4 Hz, 1H),2.18-2.07 (m, 2H), 1.70 (d, J = 11.3 Hz, 2H) and 1.43- 1.35 (m, 1H) ppm620 B A 400.41 1.92 621 A A 445.45 2.39 622 A A 431.42 2.46 623 A A435.4 3.62 H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.69 (s, 1H),8.35-8.25 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 3.9 Hz, 1H),7.51 (d, J = 6.7 Hz, 1H), 5.02-4.60 (m, 3H), 4.37-4.20 (m, 3H),3.62-3.40 (m, 2H), 3.17- 2.62 (m, 2H), 2.10 (s, 1H) and 1.85- 1.60 (m,3H) ppm 624 A B 378.15 2.49 MeOH d4 8.8 (d, 1H); 8.2 (d, 1H); 8.1 (s,1H); 7.9 (d, 1H); 4.2 (dd, 1H_); 3.6 (dt, 1H); 3.4 (dd, 1H); 2.2 (bd,1H); 2.05 (bd, 1H); 1.8 (dr, 1H); 1.6 (m, 1H); 1.4 (m, 2H). 625 A A378.34 2.42 MeOH d4 8.8 (d, 1H); 8.2 (d, 1H); 8.1 (s, 1H); 7.9 (d, 1H);4.2 (dd, 1H_); 3.6 (dt, 1H); 3.4 (dd, 1H); 2.2 (bd, 1H); 2.05 (bd, 1H);1.8 (dr, 1H); 1.6 (m, 1H); 1.4 (m, 2H). 626 A A 390.39 4.05 H NMR (300.0MHz, CDCl3) d 8.87 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1 H), 8.17(d, J = 2.7 Hz, 1H), 8.03 (d, J = 3.5 Hz, 1H), 7.28(CDCl3), 6.8 (s, 1H),4.67 (m, 1H), 2.1-1.88 (m, 4H), 1.8-1.50 (m, 7H), 0.99 (t, J = 7.5 Hz,3H) ppm 627 A A 388.36 4.01 H NMR (300.0 MHz, CDCl3) d 9.65(diasteromer 1) (s, 1 H), 8.97 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.15(d, J = 2.7 Hz, 1H), 8.05 (d, J = 3.4 Hz, 1H), 7.28(s, CDCl3), 6.75 (s,1H), 6.06 (dd, J = 10.7, 17.3 Hz, 1H), 5.32 (d, J = 3.9 Hz, 1H), 5.18(d, J = 10.8 Hz, 1H), 4.66 (qn, J = 4.0 Hz, 1H), 2.08-1.86 (m, 4H),1.79- 1.61 (m, 6H), 1pp 628 A A 388.37 3.65 H NMR (300.0 MHz, CDCl3) d9.62 (diasteromer 2) (s, 1H), 8.95 (s, 1H), 8.34 (3, 1H), 8.20 (s, 1H),8.10(s, 1H), 7.28(s, CDCl3), 6.03 (dd, J = 10.7, 17.3 Hz, 1H), 5.39-5.30(m, 1H), 5.10 (d, J = 10.7 Hz, 1H), 4.87-4.81 (m, 1H), 4.76-4.64 (m,1H), 2.29-2.24 (m, 2H), 2.19-2.02 (m, 2H), 1.84-1.78 (m, 3H), 1.62-1.21(m, 3H), ppm 629 A A 446.23 4.45 630 A A 390.36 3.95 H NMR (300.0 MHz,MeOD) d 8.72 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H),4.65-4.60 (m, 1H), 2.66 (t, J = 11.3 Hz, 1H), 2.46 (d, J = 10.2 Hz, 1H),2.17-2.04 (m, 3H) and 1.57- 1.44 (m, 4H) ppm 631 A A 378.15 3.1 632 A A378.15 2.97 633 A A 473.42 3.25 H NMR (300.0 MHz, MeOD) d 8.64 (d, J =2.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.5Hz, 1H), 4.39 (t, J = 11.9 Hz, 1H), 3.93-3.82 (m, 3H), 3.54-3.30 (m,2H), 2.52-2.43 (m, 1H), 2.37-2.33 (m, 1H), 2.20 (d, J = 11.6 Hz, 1H),2.01 (d, J = 11.3 Hz, 2H), 1.90-1.88 (m, 1H), 1.83-1.63 (m, 4H) and1.59- 1.26 (m, 3H) ppm 634 A A 433.21 3.47 H NMR (300.0 MHz, MeOD) d8.61 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.29(d, J = 5.5 Hz, 1H), 4.37 (t, J = 11.2 Hz, 1H), 3.95 (s, 1H), 3.80 (s,2H), 2.42 (t, J = 5.5 Hz, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.03 (d, J =11.0 Hz, 2H) and 1.76- 1.29 (m, 4H) ppm 635 A A 459.38 3.12 H NMR (300.0MHz, MeOD) d 8.48- 8.45 (m, 2H), 8.29-8.23 (m, 2H), 4.84 (d, J = 6.0 Hz,1H), 4.38 (d, J = 6.0 Hz, 1H), 4.26-4.23 (m, 1H), 3.96 (s, 1H),3.77-3.62 (m, 2H), 2.36 (s, 1H), 2.18 (d, J = 11.5 Hz, 1H), 2.02 (d, J =12.3 Hz, 2H), 1.70-1.25 (m, 4H) and 1.59 (s, 3H) ppm 636 A A 473.4 3.12H NMR (300.0 MHz, MeOD) d 8.64 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.36(d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.44-4.36 (m, 1H), 3.96-3.87 (m, 3H), 3.47-3.37 (m, 2H), 2.49-2.35 (m, 2H), 2.21 (d, J = 12.4Hz, 1H), 2.02 (d, J = 11.9 Hz, 2H) and 1.83-1.23 (m, 8H) ppm 637 A A474.43 2.39 H NMR (300.0 MHz, MeOD) d 8.68 (s, 1H), 8.62 (s, 1H), 8.40(s, 1H), 8.33 (d, J = 4.7 Hz, 1H), 4.44-4.35 (m, 2H), 4.21 (d, J = 12.2Hz, 1H), 4.04- 3.92 (m, 2H), 3.58 (d, J = 12.3 Hz, 1H), 3.23-3.08 (m,2H), 2.37 (d, J = 8.1 Hz, 1H), 2.23 (d, J = 11.1 Hz, 1H), 2.05 (d, J =9.7 Hz, 2H), 1.72 (m, 2H) and 1.59-1.44 (m, 2H) ppm 638 A A 459.37 3.77H NMR (300.0 MHz, MeOD) d 8.55 (d, J = 1.0 Hz, 1H), 8.46-8.45 (m, 1H),8.29-8.27 (m, 2H), 4.28 (d, J = 6.1 Hz, 2H), 4.00-3.87 (m, 3H), 2.36-2.16 (m, 3H), 2.00-1.91 (m, 5H) and 1.75-1.41 (m, 4H) ppm 639 C C 472.462.39 H NMR (300.0 MHz, MeOD) d 8.66 (s, 1H), 8.60 (s, 1H), 8.38 (s, 1H),8.31 (d, J = 4.7 Hz, 1H), 4.43-4.36 (m, 1H), 3.98-3.91 (m, 1H), 3.43 (d,J = 10.3 Hz, 2H), 3.03 (t, J = 10.6 Hz, 2H), 2.60 (s, 1H), 2.38 (d, J =10.2 Hz, 1H), 2.21 (d, J = 10.6 Hz, 1H), 2.07- 1.92 (m, 6H) and1.74-1.30 (m, 4H) ppm 640 A A 447.41 3.37 H NMR (300.0 MHz, MeOD) d 8.69(diasteromer 1) (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz,1H), 8.29 (d, J = 5.6 Hz, 1H), 4.43 (t, J = 11.9 Hz, 1H), 4.14 (q, J =6.1 Hz, 1H), 3.94 (t, J = 11.9 Hz, 1H), 2.40-2.19 (m, 4H), 2.03 (d, J =8.2 Hz, 2H), 1.78-1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J = 6.1Hz, 3H) ppm 641 A A 447.41 3.47 H NMR (300.0 MHz, MeOD) d 8.69(diasteromer 2) (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz,1H), 8.29 (d, J = 5.6 Hz, 1H), 4.43 (t, J = 11.9 Hz, 1H), 4.14 (q, J =6.1 Hz, 1H), 3.94 (t, J = 11.9 Hz, 1H), 2.40-2.19 (m, 4H), 2.03 (d, J =8.2 Hz, 2H), 1.78-1.69 (m, 1H), 1.59-1.44 (m, 3H) and 1.18 (d, J = 6.1Hz, 3H) ppm 642 A A 433.38 3.52 H NMR (300.0 MHz, MeOD) d 8.68 (s, 1H),8.56 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1H), 4.47-4.40 (m, 1H), 4.15 (s, 1H), 3.98 (m, 1H), 2.41 (s, 1H), 2.23 (d, J =10.6 Hz, 1H), 2.04 (d, J = 11.0 Hz, 2H) and 1.77-1.36 (m, 7H) ppm 643 AA 404.36 3.3 H NMR (300.0 MHz, MeOD) d 8.98 (d, J = 2.3 Hz, 1H), 8.45(s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 5.26-5.22(m, 1H), 2.17- 2.10 (m, 1H), 1.87-1.82 (m, 4H), 1.68-1.59 (m, 3H) and1.36 (s, 3H) ppm 644 C C 418.4 3.37 H NMR (300.0 MHz, MeOD) d 8.87 (d, J= 2.3 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 5.6Hz, 1H), 5.26-5.23 (m, 1H), 2.14- 2.09 (m, 1H), 1.96-1.72 (m, 6H), 1.59(s, 3H) and 0.87 (t, J = 7.4 Hz, 3H) ppm 645 A A 418.41 3.37 H NMR(300.0 MHz, MeOD) d 8.87 (d, J = 2.3 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J =2.3 Hz, 1H), 8.30 (d, J = 5.6 Hz, 1H), 5.25-5.23 (m, 1H), 2.17- 2.09 (m,1H), 1.98-1.74 (m, 6H), 1.58 (m, 3H) and 0.87 (t, J = 7.4 Hz, 3H) ppm646 A A 392.35 3.35 H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.71 (d, J= 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20-8.15 (m, 2H), 4.57-4.54(m, 1H), 4.4-4.3(s, 1H), 4.08-4.01 (m, 1H), 3.37-3.29 (m, 2H), 3.17 (d,J = 5.3 Hz, H), 2.50(qn, J = 1.7 Hz DMSO), 1.99 (s, 1H), 1.91 (d, J =3.6 Hz, H), 1.77- 1.65 (m, 6H), 1.59 (d, J = 7.5 Hz, 1H). 647 A A 474.43.59 H NMR (300.0 MHz, MeOD) d 8.56 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H),8.30 (t, J = 5.6 Hz, 1H), 8.31 (s, 1H), 4.26 (t, J = 11.2 Hz, 1H), 3.82(t, J = 11.1 Hz, 1H), 3.65-3.61 (m, 4H), 3.39- 3.36 (m, 4H), 2.36 (d, J= 10.0 Hz, 1H), 2.17 (d, J = 12.0 Hz, 1H), 2.02 (d, J = 10.2 Hz, 2H) and1.70-1.32 (m, 4H) ppm 648 A A 489.38 3.67 H NMR (300.0 MHz, MeOD) d 8.65(s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.28 (dd, J= 2.9, 5.5 Hz, 1H), 4.39 (s, 1H), 4.06-3.54 (m, 7H), 2.55-2.38 (m, 2H),2.19 (d, J = 10.7 Hz, 1H), 2.03-1.99 (m, 3H) and 1.69-1.24 (m, 5H) ppm649 A A 475.37 3.32 H NMR (300.0 MHz, MeOD) d 8.79 (d, J = 2.3 Hz, 1H),8.51 (s, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 5.22(dd, J = 4.4, 6.0 Hz, 1H), 4.53-4.45 (m, 1H), 4.21-3.50 (m, 5H),2.52-2.43 (m, 1H), 2.27- 2.04 (m, 5H) and 1.72-1.27 (m, 4H) ppm 650 A A461.38 3.79 H NMR (300.0 MHz, MeOD) d 8.56- 8.54 (m, 2H), 8.34 (s, 1H),8.30 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 11.4 Hz, 1H), 3.93 (t, J = 11.6Hz, 1H), 3.54 (s, 2H), 2.34 (d, J = 10.8 Hz, 1H), 2.18 (d, J = 11.4 Hz,1H), 2.01 (d, J = 11.3 Hz, 2H), 1.73-1.37 (m, 4H) and 1.15 (s, 6H) ppm651 A A 473.41 4.1 H NMR (300.0 MHz, MeOD) d 8.56- 8.51 (m, 2H),8.33-8.29 (m, 2H), 4.30 (d, J = 3.0 Hz, 1H), 3.98 (dd, J = 11.5, 23.4Hz, 2H), 3.83-3.79 (m, 1H), 3.55 (t, J = 8.9 Hz, 1H), 2.35 (d, J = 11.1Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.03-1.90 (m, 4H) and 1.73- 1.37 (m,8H) ppm 652 A A 459.41 3.86 H NMR (300.0 MHz, MeOD) d 8.72 (d, J = 2.3Hz, 1H), 8.56 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 5.6 Hz,1H), 4.51-4.43 (m, 1H), 4.02- 3.88 (m, 3H), 3.86-3.78 (m, 2H), 3.07-3.02(m, 1H), 2.42 (d, J = 7.5 Hz, 1H), 2.25 (d, J = 12.0 Hz, 1H), 2.19-2.06(m, 4H) and 1.79-1.35 (m, 4H) ppm 653 A A 418.4 3.37 H NMR (300.0 MHz,MeOD) d 8.87 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J = 1.8 Hz,1H), 8.01 (d, J = 3.7 Hz, 1H), 4.90 (m, 1H), 2.12 (m, 2H), 1.76-1.58 (m,7H) and 0.86 (t, J = 7.3 Hz, 3H) ppm 654 B B 411.37 2.87 655 A A 376.393.93 H NMR (300.0 MHz, CDCl3) d 10.63 (diasteromer 1) (s, 1H), 8.85-8.82(m, 1H), 8.27 (dd, J = 2.4, 12.5 Hz, 1H), 8.17-8.14 (m, 1H), 8.03 (d, J= 3.4 Hz, 1H), 7.28 (s, H), 4.84 (d, J = 6.3 Hz, 1H), 4.58 (dq, J = 3.9,15.7 Hz, 1H), 2.26 (d, J = 12.0 Hz, 2H), 2.09-1.95 (m, 2H), 1.84- 1.75(m, 3H), 1.47-1.32 (m, 5H) and 1.22 (td, J = 12.4, 5.2 Hz, 1H) ppm 656 AA 376.38 4.01 H NMR (300.0 MHz, CDCl3) d 9.54 (diasteromer 2) (s, 1H),8.86 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.7 Hz,1H), 8.04 (d, J = 3.5 Hz, 1H), 7.28 (s, H), 6.66 (s, 1H), 4.62-4.59 (m,1H), 1.96-1.88 (m, 4H), 1.81 (dd, J = 4.5, 14.9 Hz, 2H) and 1.68-1.57(m, 5H) ppm 657 C C 394.41 2.97 H NMR (300.0 MHz, DMSO) d 12.41 (s, 1H),8.80 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.17(d, J = 4.0 Hz, 1H), 7.64 (s, 1H), 4.80- 4.50 (m, 3H), 4.47 (dd, J =7.5, 14.8 Hz, 1H), 3.89 (dd, J = 5.3, 6.3 Hz, 1H), 3.77 (dd, J = 5.1,5.0 Hz, 1H), 3.50-3.37 (m, 2H), 2.36-2.24 (m, 1H), 2.04 (dd, J = 8.3,13.5 Hz, 1H), 1.99 (s, 1H), 1.27 (td, J = 8.4, 4.4 Hz, 1H) and 1.21 (s,1H) ppm 658 A A 459.29 3.5 659 A A 445.21 3.41 660 A A 445.21 3.35 661 AA 395.17 2.13 662 A A H NMR (300.0 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd,J = 2.8, 9.8 Hz, 1H), 8.27 (q, J = 1.3 Hz, 1H), 8.21 (d, J = 2.7 Hz,1H), 8.16 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 4.49 (m, 1H),4.39 (d, J = 4.0 Hz, 1H), 4.24-4.21 (m, 1H), 3.64-3.61 (m, 1H), 3.05-3.02 (m, 1H), 2.77 (t, J = 9.7 Hz, 1H), 2.36 (ddd, J = 4.8, 12.7, 12.7Hz, 2H), 2.18-2.12 (m, 2H), 1.95-1.91 (m, 1H), 1.76-1.72 (m, 1H) and1.66- 1.41 (m, 2H) ppm 663 A A 445.34 2.64 664 A A 431.26 2.48 665 A A431.26 2.53 666 D 428.3 2.6 667 D 414.5 1.4 668 A 429.3 3.51 H NMR(300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.18-8.16 (m, 2H), 7.38 (d, J = 7.7 Hz, 1H), 4.22- 4.17(m, 1H), 3.31-3.16 (m, 3H), 2.90 (m, 1H), 2.40 (t, J = 10.2 Hz, 2H),2.00-1.95 (m, 1H), 1.77-1.60 (m, 2H) and 1.50-1.38 (m, 1H) ppm 669 A A386.08 2.26 H NMR (300.0 MHz, DMSO) d 12.31 (s, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19-8.17 (m, 2H), 7.47 (d, J = 7.7Hz, 1H), 4.30- 4.20 (m, 1H), 3.80 (s, 2H), 3.07-3.03 (m, 1H), 2.82-2.73(m, 1H), 2.29- 2.10 (m, 2H), 2.05-1.96 (m, 1H), 1.87-1.65 (m, 2H) and1.49-1.40 (m, 1H) ppm 670 C C 559.42 3.57 H NMR (300.0 MHz, MeOD) d 8.64(d, J = 2.3 Hz, 1H), 8.40 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.29 (d, J= 5.0 Hz, 1H), 6.96 (m, 1H), 4.84-4.80 (m, 1H), 4.34 (m, 1H), 4.29-4.19(m, 3H), 3.54-3.47 (m, 1H), 3.15-3.07 (m, 1H), 2.68-2.58 (m, 1H), 1.92(s, 3H), 1.59-1.51 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm 671 C C 531.4 3.14 H NMR (300.0MHz, MeOD) d 8.66 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J = 2.3Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.97 (m, 1H), 4.82-4.79 (m, 1H), 4.34(m, 1H), 4.25 (dd, J = 7.6, 10.1 Hz, 1H), 3.54-3.47 (m, 2H), 3.11-3.04(m, 1H), 2.65-2.57 (m, 1H), 1.91 (s, 3H), 1.59 (m, 4H), 0.95 (t, J = 7.4Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm

TABLE 2 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of FIGS. 4 and 5:Comp. Nos. IC₅₀ EC₅₀ LCMS_Plus LCMS_RT NMR 672 A A 432.28 3.83 673 A A448.28 3.81 674 A A 405.15 3.16 675 C C 428.32 2.2 676 A A 445.34 2.45677 A A 404.38 3.32 H NMR (300.0 MHz, MeOD) d 8.93 (d, J = 2.4 Hz, 1H),8.21-8.19 (m, 2H), 7.97 (d, J = 4.0 Hz, 1H), 4.81 (dd, J = 2.8, 9.4 Hz,1H), 2.24-2.16 (m, 1H), 2.11-2.05 (m, 1H), 1.74 (m, 2H), 1.63-1.52 (m,4H) and 1.26 (s, 3H) ppm 678 A A 388.44 3.13 H NMR (300.0 MHz, MeOD) d8.67 (dd, J = 2.4, 9.1 Hz, 1H), 8.47 (s, 1H), 8.34-8.31 (m, 2H),5.27-5.23 (m, 1H), 2.12-2.04 (m, 1H), 1.88- 1.80 (m, 4H), 1.66-1.56 (m,3H) and 1.35 (s, 3H) ppm 679 A A 471.06 3.28 680 A A 471.19 3.31 681 A A447.5 3.65 H NMR (300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.49 (s,1H), 8.36 (t, J = 2.2 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 4.42 (t, J =3.8 Hz, 1H), 3.89 (t, J = 3.5 Hz, 1H), 2.33 (d, J = 6.0 Hz, 1H), 2.22(d, J = 11.4 Hz, 1H), 2.00 (d, J = 11.8 Hz, 2H), 1.78- 1.39 (m, 4H) and1.34 (d, J = 8.3 Hz, 6H) ppm 682 A A 473.49 3.96 H NMR (300.0 MHz, MeOD)d 8.68 (d, J = 1.7 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 4.47-4.38 (m, 1H), 3.94-3.87 (m, 3H),2.33- 2.19 (m, 3H), 2.04-1.88 (m, 3H), 1.90-1.73 (m, 2H), 1.73-1.41 (m,4H) and 1.36 (d, J = 8.6 Hz, 3H) ppm 683 A A 417.49 3.85 H NMR (300.0MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.3Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.46-4.36 (m, 1H), 3.95- 3.87 (m,1H), 2.35 (d, J = 11.7 Hz, 1H), 2.23-2.16 (m, 3H), 2.02 (d, J = 10.5 Hz,2H), 1.77-1.64 (m, 1H), 1.58-1.43 (m, 2H), 1.40-1.23 (m, 1H) and 1.11(t, J = 7.6 Hz, 3H) ppm 684 A A 429.49 3.86 H NMR (300.0 MHz, MeOD) d8.61 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.29(d, J = 5.6 Hz, 1H), 4.42-4.32 (m, 1H), 3.96- 3.88 (m, 1H), 2.35 (d, J =11.7 Hz, 1H), 2.19 (d, J = 12.0 Hz, 1H), 2.04- 2.00 (m, 2H), 1.72-1.27(m, 5H) and 0.88-0.70 (m, 4H) ppm 685 A A 431.49 3.87 H NMR (300.0 MHz,MeOD) d 8.60 (d, J = 2.3 Hz, 1H), 8.56-8.52 (m, 1H), 8.33 (dd, J = 2.3,5.7 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.39-4.30 (m, 1H), 3.94-3.86 (m,1H), 2.48- 2.34 (m, 2H), 2.17 (d, J = 11.8 Hz, 1H), 1.99 (d, J = 11.8Hz, 2H), 1.71- 1.67 (m, 1H), 1.62-1.27 (m, 3H) and 1.10 (d, J = 6.1 Hz,6H) ppm 686 A A 443.49 3.99 H NMR (300.0 MHz, MeOD) d 8.62 (d, J = 2.3Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 5.6 Hz,1H), 4.43-4.32 (m, 1H), 4.00- 3.92 (m, 1H), 2.31 (d, J = 11.8 Hz, 1H),2.21 (d, J = 12.1 Hz, 1H), 2.04- 1.97 (m, 2H), 1.76-1.58 (m, 2H),1.53-1.33 (m, 2H), 1.32 (s, 3H), 1.18-1.03 (m, 2H) and 0.63-0.55 (m, 2H)ppm 687 A C 450.2 3.43 688 A A 475.41 4.65 689 A A 445.47 3.7 H NMR(300.0 MHz, MeOD) d 8.69 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.37 (d, J =2.2 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 4.48-4.41 (m, 1H), 4.00- 3.93 (m,1H), 2.35 (d, J = 6.0 Hz, 1H), 2.22 (d, J = 11.3 Hz, 1H), 2.03 (d, J =13.0 Hz, 2H), 1.74-1.35 (m, 4H), 1.18-1.14 (m, 2H) and 0.99- 0.86 (m,2H) ppm 690 A A 469.47 3.84 H NMR (300.0 MHz, DMSO) d 12.33 (s, 1H),8.70 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.6 Hz,1H), 8.17 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.27- 4.17 (m,1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.21-3.16 (m, 1H), 2.96-2.90 (m, 3H),2.33-2.20 (m, 2H), 1.99- 1.94 (m, 1H), 1.80-1.60 (m, 2H) and 1.47-1.35(m, 1H) ppm 691 A A 692 A A 420.3 3.13 693 A A 448.32 3.51 694 A A 420.32.94 695 A A 448.32 3.3 696 A A 390.42 3.29 1H NMR (300 MHz, DMSO) d12.55 (bs, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.16(s, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.94 (bs, 1H), 4.11 (bs, 1H),2.26-2.02 (m, J = 10.7 Hz, 3H), 2.00-1.69 (m, J = 32.8, 20.4 Hz, 4H),1.68-1.21 (m, 5H). 697 A A 447.49 3.91 H NMR (300.0 MHz, MeOD) d 8.71(s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.46-4.38(m, 1H), 3.69-3.61 (m, 1H), 2.37 (d, J = 11.7 Hz, 1H), 2.18 (d, J = 10.6Hz, 1H), 2.07-1.98 (m, 2H), 1.74- 1.62 (m, 1H), 1.57-1.39 (m, 2H),1.39-1.25 (m, 1H) and 1.19 (d, J = 6.1 Hz, 6H) ppm 698 A A 447.48 3.6 HNMR (300.0 MHz, MeOD) d 8.71 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 1.6 Hz,1H), 8.28 (d, J = 5.3 Hz, 1H), 4.46-4.39 (m, 1H), 3.93 (t, J = 6.4 Hz,2H), 3.62 (t, J = 11.5 Hz, 1H), 2.38 (d, J = 11.1 Hz, 1H), 2.18 (d, J =11.0 Hz, 1H), 2.07-1.99 (m, 2H), 1.71-1.49 (m, 4H), 1.35-1.22 (m, 2H)and 0.93 (s, 3H) ppm 699 A A 461.51 4.18 H NMR (300.0 MHz, MeOD) d 8.70(s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 4.46-4.39(m, 1H), 3.77 (d, J = 6.5 Hz, 2H), 3.70-3.62 (m, 1H), 2.38 (d, J = 11.8Hz, 1H), 2.18 (d, J = 10.6 Hz, 1H), 2.07-1.99 (m, 2H), 1.88-1.84 (m,1H), 1.71-1.28 (m, 4H) and 0.91 (d, J = 4.5 Hz, 6H) ppm 700 A A 433.49 4H NMR (300.0 MHz, MeOD) d 8.70 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 1.9Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.46-4.38 (m, 1H), 4.01 (q, J = 7.0Hz, 2H), 3.66 (t, J = 11.7 Hz, 1H), 2.38 (d, J = 11.3 Hz, 1H), 2.18 (d,J = 11.0 Hz, 1H), 2.07-1.99 (m, 2H), 1.75-1.62 (m, 1H), 1.57-1.39 (m,2H) and 1.36-1.19 (m, 4H) ppm 701 A A 457.48 4.03 H NMR (300.0 MHz,MeOD) d 8.69 (s, 1H), 8.49 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.27 (d, J= 5.4 Hz, 1H), 4.55 (s, 2H), 4.37 (t, J = 11.6 Hz, 1H), 3.70-3.57 (m,1H), 2.37 (d, J = 10.7 Hz, 1H), 2.17 (d, J = 11.2 Hz, 1H), 2.07-1.98 (m,2H), 1.78 (s, 3H) and 1.70-1.22 (m, 4H) ppm 702 A A 443.46 3.84 H NMR(300.0 MHz, MeOD) d 8.69 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.27 (d, J= 5.4 Hz, 1H), 4.61 (s, 1H), 4.41 (t, J = 11.7 Hz, 1H), 3.65-3.53 (m,3H), 2.37 (d, J = 8.2 Hz, 1H), 2.17 (d, J = 10.9 Hz, 1H), 2.02 (t, J =13.2 Hz, 2H) and 1.70-1.27 (m, 4H) ppm 703 A A 417.52 3.66 H NMR (300.0MHz, MeOD) d 8.54 (s, 1H), 8.39 (dd, J = 2.7, 9.1 Hz, 1H), 8.34 (s, 1H),8.29 (d, J = 5.5 Hz, 1H), 4.49-4.41 (m, 1H), 4.04-3.97 (m, 1H), 3.88 (s,2H), 3.41 (s, 3H), 2.35 (d, J = 11.8 Hz, 1H), 2.21 (d, J = 11.2 Hz, 1H),2.02 (d, J = 11.7 Hz, 2H) and 1.73-1.36 (m, 4H) ppm 704 A A 457.56 3.77H NMR (300.0 MHz, MeOD) d 8.51 (s, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.34(s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 4.41 (t, J = 11.3 Hz, 1H), 4.03 (d, J= 10.5 Hz, 1H), 3.91 (t, J = 11.3 Hz, 1H), 3.79-3.76 (m, 1H), 3.51 (d, J= 7.5 Hz, 1H), 2.31 (d, J = 11.2 Hz, 1H), 2.20 (d, J = 12.4 Hz, 1H),2.00-1.89 (m, 4H) and 1.67-1.33 (m, 8H) ppm 705 A A 403.49 3.47 H NMR(300.0 MHz, MeOD) d 8.54 (s, 1H), 8.40 (dd, J = 2.6, 9.1 Hz, 1H), 8.36(s, 1H), 8.28 (d, J = 5.5 Hz, 1H), 4.43 (t, J = 11.7 Hz, 1H), 3.68- 3.61(m, 4H), 2.39 (d, J = 11.1 Hz, 1H), 2.19 (d, J = 11.2 Hz, 1H), 2.03-1.99 (m, 2H) and 1.65-1.25 (m, 4H) ppm 706 A A 458.53 3.42 H NMR (300.0MHz, MeOD) d 8.52 (s, 1H), 8.37 (dd, J = 2.7, 9.1 Hz, 1H), 8.34 (s, 1H),8.27 (d, J = 5.6 Hz, 1H), 4.43 (t, J = 11.8 Hz, 1H), 3.81 (t, J = 11.6Hz, 1H), 3.65-3.62 (m, 4H), 3.37-3.34 (m, 4H), 2.35 (d, J = 11.7 Hz,1H), 2.22 (d, J = 11.8 Hz, 1H), 2.01 (d, J = 11.0 Hz, 2H) and 1.66- 1.29(m, 4H) ppm 707 708 A A 432.5 3.49 H NMR (300.0 MHz, MeOD) d 8.86 (d, J= 2.2 Hz, 1H), 8.47 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.31 (d, J = 5.6Hz, 1H), 5.22-5.19 (m, 1H), 2.15- 2.10 (m, 1H), 2.01-1.72 (m, 6H),1.64-1.53 (m, 3H), 1.40-1.13 (m, 2H) and 0.90 (t, J = 7.2 Hz, 3H) ppm709 A A 390.46 4.11 H NMR (300.0 MHz, CDCl3) d 9.89 (enantiomer 1, (s,1H), 8.86 (d, J = 2.1 Hz, 1H), 8.30 see 710) (s, 1H), 8.16 (d, J = 2.2Hz, 1H), 8.02 (d, J = 3.4 Hz, 1H), 7.28 (s, H), 6.81 (d, J = 5.6 Hz,1H), 4.65-4.61 (m, 1H), 2.04 (d, J = 12.8 Hz, 1H), 1.87- 1.84 (m, 3H),1.77-1.71 (m, 3H), 1.65-1.55 (m, 2H), 1.38-1.22 (m, 3H) and 0.92-0.85(m, 3H) ppm 710 A A 390.47 4.02 H NMR (300.0 MHz, CDCl3) d (enantiomer2, 10.15 (s, 1H), 8.90 (d, J = 2.3 Hz, see 709) 1H), 8.29 (dd, J = 2.4,7.3 Hz, 1H), 8.16 (d, J = 2.7 Hz, 1H), 8.05-8.02 (m, 1H), 7.30 (d, J =11.4 Hz, H), 4.85 (d, J = 8.2 Hz, 1H), 4.68-4.55 (m, 1H), 2.30-2.24 (m,2H), 2.10- 1.95 (m, 1H), 1.81-1.72 (m, 5H), 1.66-1.49 (m, 2H), 1.45-1.16(m, 3H) and 1.01-0.90 (m, 3H) ppm 711 C C 503.52 2.91 1H NMR (300 MHz,MeOD) d 8.94 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.45- 8.31 (m, 2H), 5.25(d, J = 9.4 Hz, 1H), 4.15-3.95 (m, 2H), 3.84 (t, J = 10.8 Hz, 2H), 3.52(t, J = 14.1 Hz, 3H), 3.26-3.03 (m, 3H), 2.66 (s, 2H), 2.40-2.13 (m,3H), 2.02 (d, J = 32.7 Hz, 4H), 1.82-1.46 (m, 3H). 712 A A 402.47 3.98 HNMR (300.0 MHz, DMSO) d 12.28 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.27(d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 5.98-5.84 (m, 1H), 5.06 (s, 1H), 5.02 (d, J = 2.8 Hz,1H), 4.52-4.42 (m, 1H), 4.20 (s, 1H), 2.19 (d, J = 7.3 Hz, 2H), 2.06 (d,J = 11.8 Hz, 1H), 1.95-1.77 (m, 2H), 1.57 (d, J = 12.0 Hz, 2H), 1.44 (t,J = 12.3 Hz, 1H) and 1.28-1.16 (m, 2H) ppm 713 A A 402.49 4.13 H NMR(300.0 MHz, DMSO) d 12.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (d, J= 2.4 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 7.4Hz, 1H), 6.00-5.86 (m, 1H), 5.09-5.03 (m, 2H), 4.67 (s, 1H), 4.36-4.33(m, 1H), 2.33 (d, J = 7.0 Hz, 2H), 1.86-1.70 (m, 3H) and 1.65- 1.35 (m,5H) ppm 714 A A 435.34 3.3 715 A A 491.39 3.68 716 A A 477.37 3.75 717 AA 436.48 3.71 H NMR (300.0 MHz, DMSO) d 12.28 (d, J = 2.0 Hz, 1H), 8.79(dd, J = 2.4, 5.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.7Hz, 1H), 8.12 (dd, J = 1.5, 4.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 4.73(t, J = 3.9 Hz, 1H), 4.55-4.51 (m, 2H), 3.85- 3.82 (m, 1H), 2.02-1.87(m, 3H), 1.72-1.41 (m, 5H) and 1.31-1.19 (m, 2H) ppm 718 A A 436.49 3.6H NMR (300.0 MHz, DMSO) d 12.29 (s, 1H), 8.71 (t, J = 2.3 Hz, 1H), 8.27(d, J = 2.4 Hz, 1H), 8.19 (dd, J = 2.8, 4.5 Hz, 1H), 8.15 (t, J = 3.7Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.77 (dd,J = 3.8, 10.5 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 4.32 (m, 1H), 3.86 (m,1H), 2.00-1.97 (m, 2H), 1.82-1.63 (m, 4H) and 1.59-1.45 (m, 4H) ppm 719A A 443.5 4.07 H NMR (300.0 MHz, DMSO) d 12.58 (s, 1H), 8.68 (d, J = 2.2Hz, 1H), 8.36-8.23 (m, 4H), 7.81 (t, J = 5.5 Hz, 1H), 4.17 (d, J = 7.5Hz, 1H), 2.94 (t, J = 6.0 Hz, 2H), 2.43-2.35 (m, 1H), 2.14-1.22 (m, 8H),0.91- 0.80 (m, 1H), 0.40-0.31 (m, 2H) and 0.20-0.10 (m, 2H) ppm 720 A A459.5 3.99 H NMR (300.0 MHz, DMSO) d 12.72 (s, 1H), 8.65 (s, 1H), 8.54(s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.39- 8.37 (m, 2H), 4.42-4.08 (m,3H), 4.02-3.88 (m, 2H), 3.64-3.57 (m, 1H), 3.18-3.12 (m, 3H) and 2.12-1.19 (m, 9H) ppm 721 A A 417.5 3.93 H NMR (300.0 MHz, DMSO) d 12.31 (s,1H), 8.72 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H),8.14 (d, J = 4.0 Hz, 1H), 7.71 (s, 1H), 7.53 (d, 1H), 4.19-4.06 (m, 1H),3.05 (dd, J = 5.6, 7.1 Hz, 2H), 2.33 (m, 1H), 2.13-1.20 (m, 8H) and 0.98(t, 3H) ppm 722 A A 447.52 4.11 H NMR (300.0 MHz, DMSO) d 13.14 (s, 1H),9.50-9.45 (m, 1H), 9.26 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.49 (d, J =5.1 Hz, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 5.60 (s, H), 5.50 (s, 1H), 4.39(s, 1H), 2.94 (d, J = 7.3 Hz, 1H), 2.81 (qn, J = 6.3 Hz, 1H), 2.51 (s,H), 2.32 (d, J = 7.0 Hz, 2H), 2.08 (s, 2H), 1.87-1.64 (m, 4H), 1.17 (t,J = 7.2 Hz, 3H) and −0.00 (s, H) ppm 723 A A 445.5 4.03 1H NMR (300 MHz,MeOD) d 8.66 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J = 2.2 Hz,1H), 8.29 (d, J = 5.6 Hz, 1H), 4.51-4.28 (m, 1H), 4.01- 3.80 (m, 1H),2.40-2.15 (m, 2H), 2.11-1.86 (m, 2H), 1.84-1.26 (m, 4H), 1.18 (s, 9H)724 A A 428.45 3.69 1H NMR (300 MHz, MeOD) d 8.69 (d, J = 1.9 Hz, 1H),8.53 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 5.3 Hz, 1H),4.52-4.34 (m, 1H), 4.02- 3.84 (m, J = 11.5 Hz, 1H), 3.52 (s, 2H), 2.40(d, J = 12.0 Hz, 1H), 2.22 (d, J = 10.9 Hz, 1H), 2.14-1.97 (m, 2H),1.81-1.23 (m, 4H). 725 A A 446.48 2.47 1H NMR (300 MHz, MeOD) d 8.73 (d,J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.37 (t, J = 7.8 Hz, 1H),8.31 (d, J = 5.2 Hz, 1H), 4.56-4.37 (m, 1H), 4.13-3.98 (m, 1H), 3.93 (s,2H), 2.92 (d, J = 3.6 Hz, 6H), 2.43 (d, J = 12.4 Hz, 1H), 2.22 (d, J =12.4 Hz, 1H), 2.07 (t, J = 13.1 Hz, 2H), 1.83-1.24 (m, 4H). 726 A A443.53 3.92 1H NMR (300 MHz, MeOD) d 8.61 (d, J = 2.3 Hz, 1H), 8.53 (s,1H), 8.35 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.47-4.24 (m,1H), 4.01- 3.77 (m, 1H), 3.14-2.98 (m, 1H), 2.41-1.01 (m, 14H). 727 A A457.51 4.04 1H NMR (300 MHz, MeOD) d 8.68 (d, J = 2.3 Hz, 1H), 8.52 (s,1H), 8.36 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 4.51-4.30 (m,1H), 4.04- 3.80 (m, 1H), 3.25-3.04 (m, 1H), 2.39 (d, J = 20.1 Hz, 1H),2.22 (d, J = 12.3 Hz, 1H), 2.02 (d, J = 12.9 Hz, 2H), 1.94-1.24 (m, 4H),1.12 (dd, J = 10.1, 3.0 Hz, 6H), 1.04-0.94 (m, J = 9.4, 4.3 Hz, 1H),0.75-0.62 (m, 1H). 728 A A 459.56 4.17 1H NMR (300 MHz, MeOD) d 8.68 (d,J = 2.3 Hz, 1H), 8.49 (d, J = 22.9 Hz, 1H), 8.36 (t, J = 5.8 Hz, 1H),8.28 (d, J = 5.6 Hz, 1H), 4.53-4.27 (m, J = 11.6, 8.2, 3.7 Hz, 1H),4.02- 3.83 (m, J = 15.7, 7.7 Hz, 1H), 2.37 (d, J = 12.0 Hz, 1H), 2.22(d, J = 12.1 Hz, 1H), 2.06 (d, J = 14.0 Hz, 2H), 2.06 (s, 2H), 1.82-1.15(m, 4H), 1.01 (s, 9H). 729 A A 486.54 2.78 730 A A 488.52 3.82 731 C C(400 MHz, DMSO-d6): 12.33 (br s, exchanged with D2O, 2H), 8.72 (d, J =1.6 Hz, 1H), 8.27(d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J = 3.6 Hz,1H), 7.47(d, J = 7.2 Hz, exchanged with D2O, 1H), 4.04-4.02 (m, 1H),2.17- 2.00 (m, 5H), 1.63-1.39 (m, 4 H). 732 A A (400 MHz, CDCl3):12.33(s, 1H), 8.75(d, J = 2.4 Hz, 1H), 8.28(d, J = 2.4 Hz, 1H), 8.18(s,1H), 8.12(d, J = 4 Hz, 1H), 7.49(d, J = 8 Hz, 1H), 4.3(t, J = 5.2 Hz,1H), 4.04-3.97(m, 1H), 3.48- 3.43(m, 1H), 3.38-3.34(m, 2H), 2.09- 2.0(m,1H), 1.95-1.93(m, 1H), 1.81- 1.25(m, 7H). 733 A A (400 MHz, DMSO-d6):12.33(br s, exchanged with D2O, 1H), 8.27(d, J = 2 Hz, 1 H), 8.19(s,1H), 8.11(d, J = 3.6 Hz, 1H), 7.39(d, J = 6.4 Hz, Exchanged with D2O,1H), 4.05(br s, 1H), 2.39(s, 1H), 2.14-2.12(m, 2H), 1.77-1.61(m, 6H).734 A A 443.4 3.39 1H NMR (300 MHz, MeOD) d 8.71 (d, J = 2.3 Hz, 1H),8.49 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.45(s, 1H), 3.91 (s, 1H), 3.77-3.50 (m, 2H), 2.35 (d, J = 10.0 Hz, 1H),2.22 (d, J = 11.9 Hz, 1H), 2.02 (d, J = 11.7 Hz, 2H), 1.71 (d, J = 14.0Hz, 1H), 1.38 (tdd, J = 16.2, 11.9, 4.6 Hz, 6H), 1.08 (t, J = 5.5 Hz,3H), 1.04-0.94 (m, 1H), 0.61-0.49 (m, 1H). 735 A A 529.46 4.62 736 A A489.4 4.56 737 A A 485.44 4.57 738 A A 439.37 3.31 1H NMR (300 MHz,MeOD) d 8.60 (d, J = 37.9 Hz, 1H), 8.33 (d, J = 23.9 Hz, 1H), 7.64 (d, J= 8.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.00 (t, J = 54.0 Hz, 1H), 4.42(s, 1H), 4.01 (s, 1H), 2.47-2.31 (m, 2H), 2.23 (d, J = 10.9 Hz, 1H),2.12-1.97 (m, 2H), 1.77-1.17 (m, 5H), 0.95-0.83 (m, 1H). 739 A C 486.522.16 1H NMR (300 MHz, MeOD) d 8.65 (d, J = 45.0 Hz, 1H), 8.34 (d, J =23.5 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 4.45(s, 1H), 4.01 (s, 1H), 3.72 (s, 1H), 3.45 (s, 1H), 3.10 (d, J = 11.3 Hz,1H), 2.82 (d, J = 12.1 Hz, 3H), 2.36 (s, 1H), 2.28-1.25 (m, 16H). 740 A447.53 3.98 H NMR (300 MHz, MeCD) d 8.73(s, 1H), 8.45(s, 1H), 8.37(d, J= 2.1 Hz, 1H), 7.25(d, J = 5.5 Hz, 1H), 4.89- 4.8 (m, 1H), 3.02-2.95(m,2H), 2.86(d, J = 0.5 Hz, 1H), 2.65(d, J = 12.0 Hz, 1H), 2.46(d, J = 12.2Hz, 1H), 2.03-1.98(m, 1H), 1.9-1.8(m, 1H), 1.78-1.68(m, 1H), 1.5-1.3(m,2H), 0.95(t, J = 7.3 Hz, 3H) and 0.0(s, TMS) 741 A 470.46 3.82 1H NMR(300 MHz, DMSO) d 12.32 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.27 (d, J =2.4 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7.34(d, J = 7.1 Hz, 1H), 5.77 (d, J = 2.9 Hz, 1H), 4.60 (s, 1H), 3.73 (dd, J= 10.1, 6.3 Hz, 6H), 2.30-2.15 (m, 1H), 2.04-1.86 (m, 1H), 1.85-1.50 (m,6H). 742 A 470.49 3.7 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.75 (d, J= 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.14(d, J = 4.0 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 5.38 (s, 1H), 4.55-4.36(m, 1H), 3.71 (d, J = 3.1 Hz, 3H), 3.68 (d, J = 3.2 Hz, 3H), 2.16-2.01(m, 2H), 2.00-1.72 (m, 3H), 1.71-1.41 (m, 2H), 1.39-1.18 (m, 1H). 743 AA 419.34 2.86 744 A A 419.34 2.61 745 A A 447.5 3.8 1H NMR (300 MHz,MeOD) d 8.70 (d, J = 18.1 Hz, 1H), 8.50 (s, 1H), 8.38 (d, J = 10.4 Hz,1H), 8.30 (s, 1H), 4.54 (s, 2H), 4.19 (s, 2H), 3.42 (s, 3H), 2.95 (d, J= 15.2 Hz, 3H), 2.25 (d, J = 11.8 Hz, 1H), 2.09 (s, 2H), 1.98-1.39 (m, J= 62.5 Hz, 5H). 746 A A 422.48 3.6 (racemic mixture of diastereomer 1with respect 1- OH of the cyclohexyl ring, see 755) 747 A A 448.48 3.42748 A 448.5 3.51 749 A A 422.47 3.6 750 A A 447.36 3.07 751 A A 433.352.88 752 A A 447.36 2.78 753 A A 454.4 3.32 754 A C 406.35 3.16 1H NMR(300 MHz, MeOD) d 8.70 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J =2.2 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 5.37-4.57 (m, 49H), 2.42 (dd, J =13.3, 4.2 Hz, 2H), 2.15 (d, J = 10.4 Hz, 1H), 2.07-1.87 (m, 3H), 1.77(dd, J = 18.1, 8.6 Hz, 3H). 755 A C 406.35 3.03 (racemic mixture ofdiastereomer 2 with respect 1- OH of the cyclohexyl ring, see 746) 756 AA 472.45 2.24 757 A A 399.52 3.29 1H NMR (300 MHz, MeOD) d 9.00 (d, J =7.7 Hz, 1H), 8.59 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 5.3Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 4.54-4.32 (m, 1H), 4.18-3.99 (m, 1H),3.88 (s, 2H), 3.40 (s, 3H), 2.44 (d, J = 11.6 Hz, 1H), 2.13 (d, J = 10.9Hz, 1H), 1.97 (t, J = 13.6 Hz, 2H), 1.77-1.28 (m, 4H). 758 A A 427.43.26 1H NMR (300 MHz, MeOD) d 8.71 (dd, J = 14.6, 2.9 Hz, 1H), 8.49 (s,1H), 8.38 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 4.42 (t, J = 11.9 Hz, 1H),3.95 (t, J = 11.6 Hz, 1H), 2.39 (d, J = 12.1 Hz, 1H), 2.27-2.12 (m, 1H),2.03 (d, J = 10.0 Hz, 2H), 1.95 (s, 1H), 1.70 (d, J = 13.1 Hz, 1H),1.61-1.18 (m, 8H). 759 A A 460.48 2.15 1H NMR (300 MHz, MeOD) d 8.72 (d,J = 1.8 Hz, 1H), 8.57-8.44 (m, 1H), 8.38 (d, J = 1.4 Hz, 1H), 8.29 (d, J= 5.0 Hz, 1H), 4.45 (s, 1H), 4.00 (s, 1H), 3.86 (d, J = 8.5 Hz, 1H),2.97- 2.80 (m, 7H), 2.47 (s, 1H), 2.22 (d, J = 11.5 Hz, 1H), 2.06 (d, J= 11.1 Hz, 2H), 1.84-1.19 (m, 9H). 760 A A (400 MHz, DMSO-d6): 12.35 (brs, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.29(d, J = 2 Hz, 1 H), 8.2-8.17(m,2H), 6.97(d, J = 6.8 Hz, 1H), 4.6- 4.54(m, 1H), 4.5(br s, 1H),3.58-3.48(m, 2H), 2.57(s, 1H), 2.33- 2.227(m, 2H), 1.76-1.69(m, 2H),1.61- 1.59(m, 1H), 1.43-1.32(m, 2H) 761 A A (400 MHz, DMSO-d6): 12.35(br s, 1H), 8.75(d, J = 2.4 Hz, 1H), 8.29(d, J = 2 Hz, 1H), 8.2-8.17(m,2H), 6.97(d, J = 6.8 Hz, 1H), 4.6- 4.55(m, 1H), 4.5(br s, 1H), 3.58-3.5(m, 2 H), 2.56(s, 1H), 2.33- 2.227(m, 2H), 1.76-1.69(m, 2H), 1.61-1.59(m, 1H), 1.43-1.32(m, 2H) 762 A A 406.35 3.23 763 A A 406.35 3.06 1HNMR (300 MHz, MeOD) d 8.70 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J= 2.2 Hz, 1H), 8.28 (d, J = 5.5 Hz, 1H), 5.37-4.57 (m, 49H), 3.38- 3.26(m, 26H), 2.42 (dd, J = 13.3, 4.2 Hz, 2H), 2.15 (d, J = 10.4 Hz, 1H),2.07-1.87 (m, 3H), 1.77 (dd, J = 18.1, 8.6 Hz, 3H). 764 A A 420.36 3.21H NMR (300 MHz, MeOD) d 8.70 (d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.39(d, J = 2.3 Hz, 1H), 8.30 (d, J = 5.5 Hz, 1H), 4.91-4.77 (m, 27H), 3.77(s, 3H), 3.38-3.26 (m, 39H), 2.45 (dd, J = 13.2, 3.8 Hz, 2H), 2.20 (d, J= 9.8 Hz, 1H), 2.06 (s, 1H), 2.00- 1.82 (m, 3H), 1.82-1.23 (m, 5H). 765A A 453.38 3.34 766 A A 449.41 3.4 767 A A 487.42 3.56 768 A A 486.462.24 769 A C 415.5 2.75 1H NMR (300 MHz, MeOD) d 8.84 (s, 1H), 8.31 (s,2H), 6.99 (s, 1H), 4.42 (s, 1H), 4.08 (s, 1H), 3.90 (s, 2H), 3.42 (s,3H), 2.40 (s, J = 20.9 Hz, 1H), 2.26-1.85 (m, J = 27.0 Hz, 3H),1.79-1.20 (m, 4H). 770 A A 469.44 3.22 NMR 1H (MeOH-d4): 9.0 (s, 1H),8.6 (m, 2H), 8.3 (m, 2H), 8.1 (s, 1H), 4.5 (m, 1H), 4.1 (m, 1H), 3.9 (s,3H), 1.3-2.6 (m, 10H). 771 A A 472.45 2.21 772 A A 455.43 2.97 773 A A451.4 3.31 NMR 1H (MeOH-d4): 8.7 (s, 1H), 8.5 (s, 1H), 8.3 (s, 1H), 8.2(d, 1H), 4.7 (s, 1H), 4.15-4.5 (m, 4H), 3.7 (t, 1H), 2.4 (m, 1H), 2.2(m, 1H), 2.0 (t, 2H), 1.2-1.8 (m, 4H). 774 A C 472.45 2.21 NMR 1H(MeOH-d4): 8.7 (d, 2H), 8.3 (d, 2H), 4.4 (m, 1H), 3.6-4.0 (m, 3H), 3.3(s, 3H), 2.9 (m, 3H), 2.0-2.5 (m, 6H), 1.2-1.8 (m, 4H). 775 A A 435.343.21 1H NMR (300 MHz, MeOD) d 7.40 (d, J = 2.1 Hz, 1H), 7.21 (s, 1H),7.10 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 2.71 (dt, J = 13.2,6.7 Hz, 1H), 2.55 (dt, J = 18.3, 9.2 Hz, 1H), 2.26 (s, 3H), 0.90-0.67(m, 2H), 0.58 (d, J = 13.5 Hz, 1H), 0.53-0.37 (m, 2H), 0.37-0.18 (m,1H). 776 A A 392.34 2.9 1H NMR (300 MHz, MeOD) d 7.40 (d, J = 2.1 Hz,1H), 7.21 (s, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H),2.71 (dt, J = 13.2, 6.7 Hz, 1H), 2.55 (dt, J = 18.3, 9.2 Hz, 1H), 2.26(s, 3H), 0.90-0.67 (m, 2H), 0.58 (d, J = 13.5 Hz, 1H), 0.53-0.37 (m,2H), 0.37-0.18 (m, 1H). 777 C C 410.32 2.37 778 A A 507.53 3.54 1H NMR(300 MHz, DMSO) d 12.32 (s, 1H), 8.72 (dd, J = 4.9, 2.4 Hz, 1H), 8.28(d, J = 2.4 Hz, 1H), 8.22- 8.09 (m, 2H), 7.45 (dd, J = 16.1, 8.1 Hz,1H), 6.85 (d, J = 11.9 Hz, 1H), 4.51-4.41 (m, 1H), 4.32-4.16 (m, 2H),3.84-3.71 (m, 2H), 3.60 (s, 1H), 3.26 (d, J = 2.6 Hz, 3H), 2.70- 2.56(m, J = 22.6 Hz, 1H), 2.45 (s, 1H), 2.17-1.92 (m, 2H), 1.77-1.41 (m,4H), 1.33-1.11 (m, 2H). 779 A A 433.42 3.22 1H NMR (300 MHz, MeOD) d8.72 (d, J = 2.2 Hz, 2H), 8.48 (s, 2H), 8.34 (dd, J = 23.7, 3.9 Hz, 3H),4.99 (d, J = 5.4 Hz, 3H), 4.88 (s, 1H), 4.85- 4.67 (m, 32H), 3.44-2.95(m, 44H), 2.29 (dd, J = 13.5, 4.1 Hz, 3H), 2.11 (d, J = 9.5 Hz, 2H),2.04-1.80 (m, 7H), 1.76 (s, 3H), 1.13 (t, J = 7.2 Hz, 4H). 780 A A487.36 3.57 781 A A 394.32 2.81 782 A A 424.5 3.96 783 A A 456.39 2.9784 A A 473.41 3.29 785 A A 461.44 3.59 786 A A 419.34 3.01 787 A A382.399 2.47 (400 MHz, DMSO-d6): 12.36 (s, exchanged with D2O, 1H), 8.71(d, J = 2.4 Hz, 1 H), 8.29 (d, J = 1.6 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J= 4 Hz, 1H), 7.58 (d, J = 7.2 Hz, exchanged with D2O, 1H), 4.27 (br s,1H), 2.15-2.06 (m, 6H), 1.75-1.69 (m, 2H). 788 A A 362.399 2.68 (400MHz, DMSO-d6): 12.34 (s, exchanged with D2O, 1H), 8.72 (d, J = 2.4 Hz,1H),. 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.13 (d, J =4.4 Hz, 1H), 7.5 (d, J = 6 Hz, exchanged with D2O, 1H), 4.42 (br s,exchanged with D2O, 1H), 4.04 (t, J = 3.6 Hz, 1H), 3.88 (s, 1H),1.89-1.6 ( 789 A A H NMR (300.0 MHz, DMSO) d 12.90 (s, 1H), 8.96 (s,1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.42 (d, J = 5.1 Hz, 2H), 7.85 (t, J =5.4 Hz, 1H), 4.22 (d, J = 7.8 Hz, 1H), 3.34-3.17 (m, 7H) and 2.09-1.26(m, 9H) ppm 790 A A 406.49 3.87 H NMR (300.0 MHz, CDCl3) d 14.46 (s,1H), 8.81 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.96 (t, J = 1.6 Hz, 1H),7.34 (d, J = 11.5 Hz, H), 4.59 (d, J = 3.1 Hz, 1H), 3.94 (s, 2H), 2.04-1.70 (m, 8H), 1.68 (m, 2H), and 0.00 (s, H) ppm 791 A A 434.38 3.26 792A A 434.38 2.9 793 A A 406.5 3.69 H NMR (300.0 MHz, CDCl3) d 9.47 (s,1H), 8.93 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.16 (d, J =2.7 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.28 (s, H), 4.85 (s, 1H), 4.75(m, 1H), 4.01-3.97 (m, 2H), 3.07 (s, 1H), 2.50 (m, 2H), 2.30 (m, 1H),2.10 (m, 1H), 1.89-1.79 (m, 4H), 1.36 (m, 3H) and 0.99 (s, 1H) ppm 794 BA 449.48 3.9 795 A A 432.39 3.86 1H NMR (300 MHz, CDCl3) d 8.80 (1 H,s), 8.25 (1 H, s), 8.0 (1 H, s), 7.95 (1 H, s), 5.2 (1 H, m), 4.25 (2 H,q), 1.95-1.45 (8 H, m), 1.25 (3 H, s), 1.15 (3 H, t) ppm. 796 A A 446.453.12 H NMR (300.0 MHz, MeOD) d 8.73 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H),8.31 (br s, 1H), 4.34 (m, 1H), 2.60- 2.56 (m, 1H), 2.27 (m, 1H), 2.08(m, 3H) and 1.89-1.78 (m, 3H) ppm 797 A A 450.5 3.86 1H NMR (300 MHz,DMSO) d 12.30 (s, 1H), 8.73 (t, J = 2.7 Hz, 1H), 8.28 (d, J = 2.4 Hz,1H), 8.18 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 3.9 Hz, 1H), 7.53 (d, J =7.6 Hz, 1H), 5.29 (d, J = 5.0 Hz, 1H), 4.79-4.65 (m, 2H), 4.37 (s, 1H),3.23-3.14 (m, 2H), 2.02 (dd, J = 40.1, 10.3 Hz, 1H), 1.91-1.64 (m, 7H),1.59-1.44 (m, 3H), 1.19 (d, J = 10.6 Hz, 3H). 798 A A 446.34 3.37 H NMR(300.0 MHz, MeOD) d 8.67 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.31 (brs, 1H), 4.47 (m, 1H), 4.21 (m, 1H), 2.41 (m, 1H), 2.22 (m, 1H),2.10-1.90 (m, 3H), 1.72 (m, 2H) and 1.50 (m, 1H) ppm 799 A A 433.43 3.01800 A A 433.42 2.66 801 A A 461.44 3.35 (racemic mixture of diastereomer1, see 802) 802 A A 461.44 2.81 (racemic mixture of diastereomer 2, see801) 803 A A 461.44 2.94 804 A A 404.3 3.45 H NMR (300.0 MHz, MeOD) d8.84 (s, H), 8.61 (s, H), 8.36 (s, H), 8.30 (d, J = 5.1 Hz, H), 5.57 (s,H), 3.5 (1 H, M), 1.97-1.3 (m, 8 H), 0.93 (s, 3H), , ppm 805 A A 403.342.98 H NMR (300.0 MHz, MeOD) d 8.85 (d, J = 2.4 Hz, H), 8.22 (d, J = 2.3Hz, H), 8.16 (s, H), 7.99 (d, J = 4.1 Hz, H), 7.86 (s, H), 3.48 (d, J =7.0 Hz, H), 2.80 (s, H), 2.15 (s, H), 2.0 (s, H), 1.86 (qn, J = 3.3 Hz,H), 1.80 (s, H), 1.74 (s, H), 1.44 (s, H). 806 A A 417.36 3.1 H NMR(300.0 MHz, CDCl3) d 9.01 (s, H), 8.77 (d, J = 2.4 Hz, H), 8.21 (d, J =2.4 Hz, H), 8.06-7.96 (m, H), 3.44 (s, H), 3.42 (d, J = 4.0 Hz, H), 3.41(t, J = 4.0 Hz, H), 2.19-1.66 (m, H), 1.97 (s, H) and 1.56 (s, H) ppm807 A A 431.37 3.24 808 C A 392.34 2.9 809 A A 392.34 2.9 1H NMR (300MHz, DMSO) d 13.10 (s, 1H), 9.20 (d, J = 2.7 Hz, 1H), 8.93- 8.67 (m,2H), 8.49 (d, J = 5.6 Hz, 1H), 8.39-8.30 (m, 0H), 4.78 (s, 1H), 3.54 (s,1H), 3.17 (s, 2H), 2.51 (s, 4H), 2.02-1.63 (m, 3H), 1.46 (dd, J = 41.3,11.6 Hz, 3H), 1.18 (s, 3H). 810 A A H NMR (300.0 MHz, DMSO) d 8.69 (d, J= 2.4 Hz, 1H), 8.21-8.18 (m, 2H), 8.10 (d, J = 4.0 Hz, 1H), 7.29 (d, J =7.6 Hz, 1H), 6.83 (s, 1H), 5.84- 5.70 (m, 1H), 5.07-5.00 (m, 2H), 4.27(t, J = 4.0 Hz, 1H), 3.50 (d, J = 7.2 Hz, 3H), 2.39 (d, J = 8.3 Hz, 3H),2.32-2.07 (m, 2H) and 1.82-1.08 (m, 5H) ppm 811 A A 447.36 3.18 812 A A447.36 2.7 813 A A 447.36 2.79 814 A A H NMR (300.0 MHz, DMSO) d 12.92(s, 1H), 9.02-8.88 (m, 2H), 8.64 (s, 1H), 8.41 (s, 2H), 4.29 (s, br 1H),4.00-3.35 (m, 8H) and 2.17- 1.27 (m, 10H) ppm 815 A A 433.35 2.92 816 AA 406.29 3.24 817 A A 439.3 1.48 818 A A 465.34 1.73 819 A A 505.3 1.47820 A A 493.3 2 821 A A (400 MHz, DMSO-d6): 12.34 (s, exchanged withD2O, 1H), 8.76(s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.14 (d, J = 4 Hz,1H), 7.54 (d, J = 6.8 Hz, exchanged withD2O, 1H), 4.71-4.66 (m, 1H),4.59(d, J = 3.2 Hz, exchanged withD2O, 1H), 4.27 (br s, 1H), 2.23-2.20(m, 1H), 1.98-1.57(m, 10H) 822 A A (400 MHz, DMSO-d6): 12.34 (s,exchanged withD2O, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.2 8d, J = 2 Hz, 1H),8.21 (s, 1H), 8.15(d, J = 3.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, exchangedwith D2O, 1H), 4.75(d, J = 3.6 Hz, exchanged withD2O, 1H), 4.49-4.44 (m,1H), 4.22-4.21 (m, 1H), 2.34-1.50 (m, 8H) 823 A A 448.39 3.67 824 A A448.39 3.05 825 A A 404.3 3.38 826 A A 404.3 3.38 H NMR (300.0 MHz,DMSO) d 12.34 (s, H), 8.74 (d, J = 2.3 Hz, H), 8.33 (d, J = 2.3 Hz, H),8.28 (d, J = 1.6 Hz, H), 8.17-8.12 (m, H), 4.34 (s, H), 4.29 (s, H),3.89 (s, H), 3.55 (d, J = 6.3 Hz, H), 3.32 (s, H), 2.50 (s, H), 2.29 (s,H), 1.95-1.90 (m, H), 1.82 (d, J = 6.6 Hz, H), 1.76 (s, H), 1.67 (s, H),1.55 (s, H), 1.44-1.42 (m, H), 1.31 (s, H), 1.23 (s, H), 1.17 (s, H),1.07 (s, H), 0.84 (d, J = 6.9 Hz, H) and −0.00 (d, J = 1.0 Hz, H) ppm827 A A 404.37 2.72 828 A A 377.37 1.9 829 A A 470.4 2.95 830 A B 392.342.98 MeOD d4: 8.8 (d, 1H); 8.5 (s, 1H); 8.4 (d, 1H); 8.3 (d, 1H); 4.5(dd, 1H); 3.6 (dd, 1H); 3.3 (dd, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.9 (m,1H); 1.6 (app t, 2H); 1.3 (m, 1H). 831 A A 392.34 2.98 MeOD d4: 8.8 (d,1H); 8.5 (s, 1H); 8.4 (d, 1H); 8.3 (d, 1H); 4.5 (dd, 1H); 3.6 (dd, 1H);3.3 (dd, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.9 (m, 1H); 1.6 (app t, 2H);1.3 (m, 1H). 832 A A 376.34 2.94 MeOD d4: 8.8 (d, 1H); 8.65 (s, 1H);8.45 (d, 1H); 8.35 (d, 1H); 4.2 (dd, 1H); 3.4 (dd, 1H); 2.2 (m, 2H); 2.0(m, 1H); 1.6 (m, 4H); 1.2 (d, 3H). 833 B A 376.34 2.94 MeOD d4: 8.8 (d,1H); 8.65 (s, 1H); 8.45 (d, 1H); 8.35 (d, 1H); 4.2 (dd, 1H); 3.4 (dd,1H); 2.2 (m, 2H); 2.0 (m, 1H); 1.6 (m, 4H); 1.2 (d, 3H). 834 A A 442.373.25 H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H),8.28 (d, J = 2.4 Hz, 1H), 8.19- 8.18 (m, 2H), 7.31 (d, J = 7.1 Hz, 1H),5.76 (s, 1H), 5.26 (t, J = 6.4 Hz, 1H), 4.58 (s, 1H), 3.87-3.74 (m, 2H),2.50 (qn, J = 1.8 Hz, H), 2.01- 1.80 (m, 3H), 1.74-1.50 (m, H) and −0.00(TMS) ppm 835 A A 442.37 2.84 H NMR (300.0 MHz, DMSO) d 12.30 (s, 1H),8.76 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.19- 8.13 (m, H),7.44 (d, J = 7.6 Hz, H), 5.22-5.17 (m, 2H), 4.48-4.45 (m, 1H), 3.80 (td,J = 15.9, 7.4 Hz, H), 3.18 (d, J = 5.2 Hz, 2H), 2.51 (s, H), 2.09 (d, J= 11.4 Hz, 1H), 2.03 (s, 1H), 1.92-1.80 (m, 1H), 1.70 (t, J = 12.3 Hz,H), 1.70-1.60 (m, 3H), 1.42 (dd, J = 9.9, 12.9 Hz, 1H), 1.26 (dd, J =11.5, 22.0 Hz, 1H) and −0.00 (s, H) ppm 836 A A 483.39 3.37 837 A A483.39 2.93 838 A C 388.37 4.02 839 A 433.4 3.69 1H NMR (300 MHz, MeOD)d 8.83 (d, J = 2.1 Hz, 1H), 8.49 (s, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.26(d, J = 5.6 Hz, 1H), 3.49-3.14 (m, 3H), 2.68 (s, 0H), 2.19 (d, J = 14.2Hz, 1H), 2.09 (d, J = 13.0 Hz, 1H), 1.96 (s, 4H), 1.76 (s, 2H), 1.49 (d,J = 41.9 Hz, 3H). 840 A 438.32 3.68 H NMR (300.0 MHz, DMSO) d 12.29 (s,1H), 8.78 (dd, J = 2.4, 6.6 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.18 (d,J = 1.9 Hz, 1H), 8.13 (dd, J = 0.8, 4.0 Hz, 1H), 7.44 (d, J = 8.1 Hz,1H), 4.83-4.78 (m, 1H), 4.52 (t, J = 3.6 Hz, 1H), 2.97-2.82 (m, 2H),2.58 (d, J = 1.4 Hz, 3H), 2.19-1.81 (m, 3H), 1.72-1.57 (m, 2H),1.54-1.32 (m, 1H) and 1.31-1.12 (m, 2H) ppm 841 A A 390.5 2.97 (400 MHz,DMSO-d6): 12.8 (br.s, exchanged with D2O, 1H), 8.68 (br.s, 1H),8.40-8.38 (m, 2H), 4.59-4.57 (m, 1H), 2.36-2.11 (m, 4H), 2.11- 2.06 (m,1H), 1.92-1.79 (m, 2H), 1.46-1.44 (m, 2H). 842 A 454.37 3.47 H NMR(300.0 MHz, DMSO) d 13.06 (s, 1H), 9.35 (d, J = 6.4 Hz, 1H), 9.10 (d, J= 2.5 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H),4.67 (d, J = 7.7 Hz, 1H), 3.41- 3.25 (m, 2H), 3.02 (s, 3H), 2.29 (d, J =11.8 Hz, 1H) and 2.08-1.35 (m, 8H) ppm 843 A A 525.43 3.58 844 A A525.43 3.09 845 A 449.41 3.36 1H NMR (300 MHz, MeOD) d 8.36 (s, 1H),8.22 (s, 1H), 8.13 (s, 1H), 4.25 (br s, 1H), 4.14-3.79 (m, 3H), 3.44 (s,3H), 2.38 (br s, 1H), 2.17 (br s, 1H), 2.09-1.92 (m, 2H), 1.79- 1.29 (m,J = 62.8 Hz, 4H). 846 A 390.399 2.91 (400 MHz, DMSO-d6): 12.61 (br.s,exchanged with D2O, 1H), 8.69 (s, 1H), 8.41-8.30 (m, 3H), 3.54-3.43 (m,2H), 2.74-2.68 (m, 1H), 2.46- 2.42 (1H), 2.15-2.08 (m, 2H), 1.82 (br.s,3H), 1.57-1.47 (m, 2H). 847 A 389.35 3.79 848 A 376.399 2.79 (400 MHz,DMSO-d6): 12.6 (br.s, exchanged with D2O, 1H), 8.70 (s, 1H), 8.40-8.30(m, 3H), 4.65-4.60 (m, 1H), 3.01-2.93 (m, 1H), 2.28- 1.95 (m, 4H),1.86-1.72 (m, 2H). 849 A 390.399 2.89 (400 MHz, DMSO-d6): 12.90 (br.s,exchanged with D2O, 1H), 9.20 (br.s, exchanged with D2O, 1H), 8.65 (s,1H), 8.44 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 2 Hz, 1H), 3.56-3.49 (m,3H), 2.85-2.80 (m, 1H), 2.01-1.89 (m, 3H), 1.77-1.67 (m, 2H), 1.44-1.39(m, 1H). 850 A (400 MHz, DMSO-d6): 12.32 (br s, exchanged with D2O, 1H),8.75 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.14 (d, J = 3.6 Hz, 1H), 7.6(d, J = 6.4 Hz, exchanged with D2O, 1H), 4.58-4.53 (m, 1H), 2.27 (d, J =7.2 Hz, 2H), 2.19- 1.67 (m, 5H), 1.36-1.29(m, 1H). 851 A A 483.39 3.6852 A A 483.39 3.05 853 A 438.36 3.58 H NMR (300.0 MHz, DMSO) d 12.29(s, 1H), 8.78 (s, 1H), 8.26- 8.18 (m, 3H), 7.44 (s, 1H), 5.05- 4.30 (m,2H), 3.08-2.74 (M, 1H) and 2.26-0.92 (m, 12H) ppm 854 A A 454.27 2.64 HNMR (300.0 MHz, DMSO) d 12.30 (s, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.27(d, J = 2.3 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H),7.47 (d, J = 7.7 Hz, 1H), 4.90 (s, 1H), 4.51 (t, J = 3.9 Hz, 1H), 3.01(s, 3H), 2.24 (d, J = 12.3 Hz, 1H), 2.09- 1.79 (m, 4H), 1.71-1.41 (m,3H) and 1.36-1.05 (m, 2H) ppm 855 A A 414.35 3 1H NMR (300 MHz, DMSO) d12.33 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.41- 8.04 (m, 3H), 7.62 (d, J= 7.4 Hz, 1H), 4.30 (s, 1H), 3.54-3.06 (m, 3H), 2.67-2.31 (m, 1H),2.23-1.33 (m, 6H) 856 A A 424.34 3.63 H NMR (300.0 MHz, CDCl3) d 8.85(q, J = 2.3 Hz, H), 8.17 (dd, J = 2.3, 21.3 Hz, 2H), 8.00 (d, J = 3.5Hz, 1H), 5.03 (s, H), 4.64-4.55 (m, 1H), 4.38 (dd, J = 4.0, 8.3 Hz, 1H),4.01- 3.88 (m, 2H), 2.45-1.90 (m, 4H), 1.51-1.25 (m, 3H) and 0.00 (s, H)ppm 857 A A 433.37 3.47 1H NMR (300 MHz, DMSO) d 13.02 (s, 1H), 9.22 (s,1H), 9.03 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.46 (d, J =5.5 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.81 (t, J = 5.8 Hz, 1H), 4.64(d, J = 8.0 Hz, 1H), 3.16-2.99 (m, 2H), 2.09-1.73 (m, 3H), 1.85 (s, 3H),1.73-1.42 (m, 3H), 1.28 (dd, J = 27.5, 10.6 Hz, 2H). 858 A A 490.36 2.78859 A A 424.41 3.8 H NMR (300.0 MHz, MeOD) d 8.73 (s, 1H), 8.17 (d, J =1.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 3.7 Hz, 1H), 4.57(s, 1H), 4.50 (d, 1H), 4.10-3.80 (m, 2H), 2.21-1.60 (m, 8H) and 0.00 (s,H) ppm 860 A A 392.34 2.82 MeOD4: 8.75 (d, 1H); 8.5 (s, 1H); 8.4 (d,1H); 8.25 (d, 1H); 7.7 (d, 1H); 7.2 (d, 1H); 4.5 (ddd, 1H); 3.65 (d,1H); 2.35 (s, 1H); 2.1 (m, 1H); 1.85 (m, 2H); 1.6 (m, 3H); 1.35 (s, 3H).861 A A 362.33 2.43 MeOD4 8.55 (dd, 1H); 8.2 (d, 2H); 8.0 (d, 1H); 7.7(d, 1H); 7.2 (d, 1H); 4.2 (ddd, 1H); 3.6, (ddd, 1H); 3.4 (dd, 1H); 2.4(s, 2H); 2.2 (m, 1H); 2.1 (m, 2H); 1.8 (m, 1H); 1.4 (m, 3H). 862 A A442.44 3.77 1H NMR (300 MHz, DMSO) d 12.28 (s, 1H), 8.75 (d, J = 2.4 Hz,1H), 8.27 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H),7.69 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.38 (s, 1H), 6.22(t, J = 2.0 Hz, 1H), 4.67 (s, 1H, OH), 4.49-4.38 (m, 1H), 4.10 (s, 2H),2.05-1.80 (m, 2H), 1.72- 1.55 (m, 2H), 1.52-1.40 (m, 2H), 1.35- 1.14 (m,2H). 863 A A 503.42 3.36 864 A A 503.42 3.46 865 A A 517.43 3.57 866 A A416.33 2.75 1H NMR (300 MHz, MeOD) d 8.53 (s, 1H), 8.38-8.30 (m, 2H),8.28 (d, J = 5.6 Hz, 1H), 4.40 (ddd, J = 11.9, 8.2, 3.9 Hz, 1H), 3.78(ddd, J = 11.9, 8.2, 3.8 Hz, 1H), 2.89 (s, 6H), 2.33 (d, J = 11.6 Hz,1H), 2.21 (d, J = 11.4 Hz, 1H), 2.05-1.96 (m, J = 6.8, 4.1 Hz, 3H),1.67-1.33 (m, 4H). 867 A A 503.35 2.79 868 A A 503.35 2.93 869 A A376.28 2.6 1H NMR (300 MHz, MeOD) d 8.65 (dd, J = 9.6, 2.8 Hz, 1H), 8.20(s, 1H), 8.17-8.09 (m, 1H), 8.01 (d, J = 4.0 Hz, 1H), 4.53 (s, 1H), 3.60(s, 2H), 1.89 (dd, J = 28.7, 12.9 Hz, 3H), 1.74-1.41 (m, 5H), 1.28 (s,3H). 870 A A 457 2.84 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.41 (dd,J = 9.9, 2.8 Hz, 1H), 8.24 (d, J = 13.1 Hz, 2H), 8.14 (d, J = 4.0 Hz,1H), 7.79 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.12 (s, 1H),3.76 (d, J = 11.2 Hz, 2H), 3.38-3.15 (m, 3H), 2.35 (dd, J = 12.6, 8.6Hz, 1H), 2.04 (dd, J = 25.4, 9.8 Hz, 2H), 1.89-0.99 (m, 10H). 871 A A438.34 2.89 872 A A 376.28 2.57 873 A A 486.46 2.98 1H NMR (300 MHz,MeOD) d 8.49 (s, 1H), 8.41 (dd, J = 9.0, 2.6 Hz, 1H), 8.35 (s, 1H), 8.28(d, J = 5.6 Hz, 1H), 4.55-4.37 (m, 1H), 3.83 (d, J = 12.8 Hz, 2H),3.59-3.43 (m, 2H), 2.50-2.28 (m, 3H), 2.22 (d, J = 10.6 Hz, 1H), 2.01(d, J = 11.6 Hz, 2H), 1.74-1.25 (m, 5H), 1.15 (d, J = 6.2 Hz, 6H). 874 AA 486.46 2.9 1H NMR (300 MHz, MeOD) d 8.51 (s, 1H), 8.42 (d, J = 9.0 Hz,1H), 8.35 (s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 4.46 (s, 1H), 3.95-3.76 (m,J = 11.0 Hz, 2H), 3.76-3.61 (m, 2H), 3.61-3.51 (m, 1H), 3.50-3.39 (m,2H), 2.43- 2.28 (m, 1H), 2.22 (d, J = 12.0 Hz, 1H), 2.01 (d, J = 11.0Hz, 2H), 1.53 (ddd, J = 44.1, 27.8, 15.6 Hz, 4H), 1.32-1.10 (m, 6H). 875A A 401.3 3.01 H NMR (300.0 MHz, DMSO) d 12.32 (s, 1H), 8.71 (d, J = 2.4Hz, 1H), 8.29-8.26 (m, 2H), 8.17 (d, J = 3.9 Hz, 1H), 7.44 (d, J = 7.7Hz, 1H), 4.31 (s, 1H), 2.85 (d, J = 5.9 Hz, 2H), 2.51 (t, J = 1.7 Hz,H), 2.08-1.98 (m, 1H), 1.77-1.64 (m, 4H), 1.50 (d, J = 6.3 Hz, 3H) and0.00 (s, H) ppm 876 A A 489.34 2.99 877 A A 489.34 2.75 878 A A 374.211.64 879 A A 483.45 2.35 880 A A 427.4 2.97 881 C C 389.27 2.03 1H NMR(300 MHz, DMSO) d 12.79 (s, 1H), 8.77 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H),8.43 (d, J = 4.8 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.52 (s, 3H), 4.29(s, 1H), 4.08 (d, J = 12.6 Hz, 1H), 3.90 (d, J = 13.7 Hz, 1H), 3.16-2.95 (m, 2H), 2.17 (d, J = 9.7 Hz, 1H), 1.92 (d, J = 8.5 Hz, 1H), 1.81-1.57 (m, 2H). 882 A A 401.3 2.73 H NMR (300.0 MHz, MeOD) d 8.86 (d, J =2.4 Hz, 1H), 8.19-8.16 (m, 2H), 7.97 (d, J = 4.0 Hz, 1H), 4.69- 4.58 (m,1H), 2.65 (s, 2H), 2.26- 1.98 (m, 3H), 1.84 (d, 1H), 1.79- 1.73 (m, 1H),1.67-1.47 (m, 2H), 1.36-1.21 (m, 1H) and 0.00 (TMS) ppm 883 A A 457.383.55 1H NMR (300 MHz, DMSO) d 12.25 (s, 1H), 8.63-8.02 (m, 4H), 7.62(dd, J = 62.6, 7.2 Hz, 2H), 3.90 (t, J = 60.4 Hz, 4H), 2.47-0.73 (m,15H). 884 E A 471.39 3.74 885 A A 420.24 3.09 886 A A 454.26 3.62 H NMR(300.0 MHz, DMSO) d 12.32 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.28-8.24(m, 2H), 8.17 (d, J = 3.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 5.34 (s,1H), 4.32 (s, 1H), 3.41 (s, 2H), 3.04 (s, 3H), 2.22 (d, J = 11.7 Hz,1H), 2.12-1.69 (m, 4H) and 1.52 (d, J = 8.7 Hz, 3H) ppm 887 A C 420.243.09 888 A A 420.36 3.93 H NMR (300.0 MHz, MeOD) d 8.81 (diastereomer 1,(d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 see 889) Hz, 1H), 8.13 (s, 1H),7.97 (d, J = 4.0 Hz, 1H), 4.50 (s, 1H), 4.28-4.18 (m, 1H), 3.72 (dd, J =4.2, 9.1 Hz, 2H), 2.02 (d, J = 6.3 Hz, 1H), 1.89-1.81 (m, 4H), 1.69-1.55(m, 3H), 1.26- 1.20 (m, 4H) and −0.00 (s, H) ppm 889 A A 420.37 3.94 HNMR (300.0 MHz, MeOD) d 8.79 (diastereomer 2, (d, J = 2.4 Hz, 1H), 8.21(d, J = 2.4 see 888) Hz, 1H), 8.12 (s, 1H), 7.99 (d, J = 4.0 Hz, 1H),4.47 (dd, J = 3.6, 7.6 Hz, 1H), 4.25-4.17 (m, 1H), 2.10 (dd, J = 3.7,13.4 Hz, 1H), 1.91-1.77 (m, 3H), 1.69-1.50 (m, 4H), 1.20 (d, J = 9.4 Hz,2H) and −0.00 (TMS) ppm 890 A A 472.42 3.6 891 A A 456.4 3.82 892 A A472.41 3.69 893 A A 486.42 3.6 894 A A 486.44 3.6 895 A A 442.42 3.7 896A A 500.42 3.77 897 A A 458.42 3.48 898 A A 472.42 3.51 899 A A 401 3.61H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.41 (dd, J = 9.8, 2.9 Hz, 1H),8.24 (d, J = 9.7 Hz, 2H), 8.13 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 7.6 Hz,1H), 7.48 (d, J = 7.4 Hz, 1H), 4.15 (s, 1H), 3.73 (s, 1H), 2.22-1.91 (m,4H), 1.82 (d, J = 11.1 Hz, 2H), 1.29 (ddd, J = 54.3, 34.3, 10.3 Hz, 4H),0.97 (t, J = 7.6 Hz, 3H). 900 A A 413 3.56 1H NMR (300 MHz, DMSO) d12.23 (s, 1H), 8.40 (dd, J = 9.9, 2.9 Hz, 1H), 8.25 (s, 1H), 8.22 (s,1H), 8.13 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.48 (d, J =7.5 Hz, 1H), 4.15 (s, 1H), 3.72 (s, 1H), 2.22-1.73 (m, 4H), 1.62-1.04(m, 5H), 0.75- 0.53 (m, 4H). 901 A A 442.37 2.97 902 A A 472.43 3.41 903A A 472.48 3.65 904 A A 472.38 2.72 905 A A 472.38 2.61 906 A A 472.382.67 907 A A 486.4 2.88 908 A A 457.35 2.53 909 A A 499.38 2.62 910 A A486.4 3.02 911 A A 506.29 2.57 912 A A 460.35 2.79 913 A A 456.39 2.98914 A A 486.4 2.79 915 A A 456.39 2.98 916 A A 500.41 3.1 917 A 454.342.54 918 A 508.34 3.38 919 A 470.4 1.59 920 A 384.34 1.74 921 A 488.381.92 922 A 481.4 1.79 H NMR (300.0 MHz, MeOD) d 8.44- 8.41 (m, 2H), 8.32(dd, J = 1.6, 2.7 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 4.42 (t, J = 11.8Hz, 1H), 3.79 (t, J = 11.6 Hz, 1H), 3.65 (td, J = 10.2, 4.7 Hz, 2H),3.54 (qn, J = 1.6 Hz, 1H), 2.97 (dt, J = 12.5, 4.2 Hz, 1H), 2.34 (d, J =10.7 Hz, 1H), 2.21 (d, J = 12.1 Hz, 1H), 2.03-1.87 (m, 4H) and 1.79-1.23 (m, 7H) ppm 923 A 499.38 1.57 H NMR (300.0 MHz, MeOD) d 8.53 (dd, J= 2.8, 9.6 Hz, 1H), 8.18-8.08 (m, 2H), 7.99 (d, J = 4.1 Hz, 1H), 4.25(dt, J = 15.2, 4.8 Hz, 1H), 4.04 (d, 2H), 3.83-3.68 (m, 1H), 2.80 (dd, J= 2.5, 25.7 Hz, 2H), 2.46-2.35 (m, 2H), 2.21 (d, J = 10.7 Hz, 1H), 1.97(s, 1H), 1.80-1.75 (m, 2H), 1.63- 1.29 (m, 3H) and 1.22 (d, J = 4.8 Hz,4H) ppm 924 A 403.34 1.77 925 C 398.35 1.75 926 A 472.38 2.08 H NMR(300.0 MHz, MeOD) d 8.76 (d, J = 2.4 Hz, H), 8.44-8.38 (m, H), 8.27 (d,J = 5.6 Hz, H), 4.87 (d, J = 5.1 Hz, H), 4.64-4.56 (m, H), 3.38- 3.19(m, H), 2.65 (s, H), 2.46 (s, H), 2.42 (s, H), 2.16 (s, H), 2.07 (t, J =12.0 Hz, H), 2.00 (s, H), 1.88 (q, J = 6.6 Hz, H), 1.88 (s, H), 1.70 (s,H) and 1.61 (d, J = 12.8 Hz, H) ppm 927 C 420.36 1.8 928 A 420.36 1.79929 431.19 1.82 H NMR (300.0 MHz, MeOD) d 8.85 (d, J = 2.4 Hz, H), 8.22(d, J = 2.3 Hz, H), 8.15 (s, H), 7.99 (d, J = 4.1 Hz, H), 7.70 (d, J =8.0 Hz, H), 7.64 (s, H), 5.49 (s, H), 5.01 (s, H), 4.95 (s, H), 4.88 (s,H), 4.56-4.47 (m, H), 3.53 (d, J = 1.7 Hz, H), 3.35-3.17 (m, H), 3.07(s, H), 2.66 (s, H), 2.36 (s, H), 2.13 (d, J = 9.6 Hz, H), 2.02- 1.98(m, H), 1.89 (s, H), 1.83-1.77 (m, H), 1.73-1.68 (m, H), 1.63 (s, H),1.49-1.42 (m, H), 1.36 (s, H), 1.28 (s, H), 1.20-1.07 (m, H) and 0.01(d, J = 3.3 Hz, H) ppm 930 417.19 1.84 H NMR (300.0 MHz, MeOD) d 8.86(d, J = 2.4 Hz, H), 8.26-8.22 (m, H), 8.15 (s, H), 8.03-7.98 (m, H),7.67 (s, H), 7.62 (s, H), 5.47 (d, J = 10.7 Hz, H), 5.09 (d, J = 6.6 Hz,H), 5.01 (s, H), 4.88 (s, H), 4.61 (s, H), 4.52 (dd, J = 7.1, 15.2 Hz,H), 4.52 (s, H), 3.72 (s, H), 3.66 (s, H), 3.60 (d, J = 7.1 Hz, H),3.54-3.43 (m, H), 3.34 (s, H), 3.31 (qn, J = 1.6 Hz, H), 3.08 (t, J =1.7 Hz, H), 2.76-2.71 (m, H), 2.13 (d, J = 12.7 Hz, H), 2.01 (d, J = 8.5Hz, H), 1.83-1.76 (m, H), 1.72- 1.67 (m, H), 1.63 (s, H), 1.42 (s, H),1.37 (d, J = 6.5 Hz, H), 1.29-1.15 (m, H), 0.98 (s, H), 0.83 (s, H),0.20 (s, H), 0.07 (s, H), 0.00 (TMS) and −0.20 (s, H) ppm 931 494.392.04 932 A A 416.44 2.93 933 A A 453.4 1.5 934 A A 476.09 1.92 935 A A478.08 1.89 936 A A 460.1 1.76 937 A A 474.6 2.02 938 A A 388.11 1.87939 A A 392.41 2.42 940 490.1 2.04 941 472.13 1.79 H NMR (300.0 MHz,MeOD) d 8.70 (d, J = 2.2 Hz, H), 8.51-8.43 (m, H), 8.33 (s, H), 8.10 (d,J = 5.6 Hz, H), 4.77 (s, H), 4.63-4.53 (m, H), 4.15 (d, J = 4.5 Hz, H),3.98-3.90 (m, H), 3.84 (t, J = 5.0 Hz, H), 3.63-3.53 (m, H), 3.48-3.41(m, H), 3.21 (s, H), 3.16 (s, H), 3.11 (s, H), 2.82 (s, H), 2.65 (s, H),2.49 (d, J = 9.8 Hz, H), 2.13-1.90 (m, H), 1.86-1.72 (m, H), 1.67 (s,H), 1.62-1.51 (m, H), 1.33 (dd, J = 6.5, 17.5 Hz, H) and −0.00 (TMS) ppm942 466.2 1.66 943 456.13 1.92 H NMR (300.0 MHz, MeOD) d 12.44 (s, H),8.49-8.46 (m, H), 8.33 (s, H), 8.23 (d, J = 5.6 Hz, H), 7.31- 7.25 (m,H), 7.19 (d, J = 7.9 Hz, H), 7.12 (s, H), 7.07 (t, J = 7.2 Hz, H), 4.90(d, J = 12.9 Hz, H), 4.81 (d, J = 6.3 Hz, H), 4.75 (s, H), 4.69 (s, H),4.60 (t, J = 11.1 Hz, H), 4.58 (s, H), 4.23 (s, H), 4.06 (d, J = 8.5 Hz,H), 3.72 (s, H), 3.54 (s, H), 3.44-3.39 (m, H), 3.32-3.25 (m, H), 3.18(t, J = 1.7 Hz, H), 3.15 (s, H), 3.08-3.07 (m, H), 2.98 (s, H), 2.65 (s,H), 2.47 (d, J = 12.5 Hz, H), 2.05 (q, J = 11.9 Hz, H), 2.00 (s, H),1.91-1.83 (m, H), 1.73 (d, J = 9.7 Hz, H), 1.64 (s, H), 1.56 (d, J =12.6 Hz, H), 1.45 (s, H), 1.37 (d, J = 6.9 Hz, H), 0.20 (s, H), 0.07 (s,H), 0.01-−0.02 (m, H), −0.20 (s, H), −2.49 (s, H) and −2.71 (s, H) ppm944 482.1 1.93 945 A A 402.399 2.23 (400 MHz, DMSO-d6): 12.35 (br s,exchanged with D2O, 1H), 9.18 (br s, exchanged with D2O, 1H), 8.75 (s,1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 3.2 Hz, 1H), 4.38 (br s,1H), 3.01 (d, J = 10 Hz, 1H), 2.8 (s, 1H), 2.58 (s, 1H), 1.68 (d, J =9.2 Hz, 1H), 1.56- 1.22 (m, 5H) 946 A A 402.399 1.88 (400 MHz, DMSO-d6):12.15 (br s, exchanged with D2O, 3H), 8.77 (d, J = 2.4 Hz, 1H), 8.28 (d,J = 2 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J = 4 Hz, 1H), 7.78 (d, J = 6 Hz,1H), 4.66-4.65 (m, 1H), 2.7-2.65 (m, 2H), 1.72 (d, J = 9.6 Hz, 1H),1.58-1.32 (m, 5H) 947 A A 402.32 3.42 H NMR (300.0 MHz, MeOD) d 8.87 (d,J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.30 (d, J =5.7 Hz, 1H), 4.73 (d, J = 3.3 Hz, 1H), 3.12 (m, 1H), 2.76 (br s, 1H),2.56 (d, J = 4.2 Hz, 1H), 1.86 (d, J = 9.5 Hz, 2H), 1.79-1.49 (complexm, 2H) and 1.51 (embedded d, J = 10.4 Hz, 2H) ppm 948 A A 417.36 3.11949 A A 417.29 2.99 950 A 430.41 3 951 A A 431.37 2.98 NMR 1H (MeOH-d6):8.7 (s, 1H), 8.5 (s, 1H), 8.35 (s, 1H), 8.3 (s, 1H), 4.5 (m, 1H), 4.3(m, 2H), 3.9 (m, 1H), 3.7 (m, 2H), 2.2 (m, 2H), 1.3-2.1 (m, 6H). 952 A A430.83 2.83 953 A A 430.43 3.17 954 A A 444.36 3.33 955 A A 458.37 3.58956 A A 429.53 3.15 H NMR (300.0 MHz, MeOD) d 8.72 (d, J = 2.2 Hz, 1H),8.49 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H),4.54-4.47 (m, 1H), 4.13 (t, J = 11.8 Hz, 1H), 3.57-3.45 (m, 2H),2.42-2.36 (m, 2H), 2.25 (m, 1H), 2.15-2.00 (m, 4H), 1.90-1.59 (m, 4H)and 1.53-1.43 (m, 1H) ppm 957 A A 544.4 3.62 958 A A 444.4 3.21 NMR 1H(MeOH-d4): conclusive with structure. 959 A A 431.37 3.21 960 A A 431.373.24 961 A A 431.37 3.05 962 A A 431.37 3.09 963 A A 445.38 3.39 964 A A445.38 3.16 965 A A 415.37 2.9 966 A A 415.37 2.9 967 A A 415.37 2.64968 A A 415.37 2.72 969 A A 415.31 2.94 970 A A 431.3 3.16 971 A A 431.33.01 972 A A 415.31 2.94 973 A A 415.31 2.95 974 A A 416.33 1.79 975 A A415.37 1.82 976 A A 415.37 1.72 977 A A 399.53 2.17

TABLE 3 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of FIG. 6 Cell Flu,MDCK Cell Influenza protection, HA(−) 30 hr ATP (All: A/PR/8 bDNA: Comp.IC50: uM) bDNA EC50 uM Nos. (Mean (All)) (Mean (All)) LCMS_Plus LCMS_RTNMR 979 A A 385.48 2.31 H NMR (300.0 MHz, MeOD) d 8.65 (dd, J = 2.8, 9.6Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J = 2.0, 2.5 Hz, 1H), 7.98 (d, J = 4.1Hz, 1H), 4.75- 4.65 (m, 1H), 2.64 (s, 2H), 2.20 (d, J = 12.6 Hz, 2H),2.01 (dd, J = 3.4, 9.8 Hz, 2H), 1.84- 1.75 (m, 1H), 1.63-1.47 (m, 2H),1.33 (dd, J = 3.6, 12.4 Hz, 1H) and 0.00 (TMS) ppm 980 A A 432.26 2.46DMSO d6: 12.5 (bs, 1H); 8.75 (d, 1H); 8.65 (d, 1H); 8.3 (m, 4H); 7.7 (m,2H); 7.2 (bs, 1H); 4.5 (bs, 1H); 2.7 (s, 3H); 2.3 9dd, 1H); 2.0 (m, 2H);1.8-1.2 (m, 8H); 0.8 (t, 3H). 981 A A 399.25 1.65 1H NMR (300 MHz, MeOD)d 8.52 (s, 1H), 8.46-8.23 (m, 3H), 4.51 (t, J = 11.9 Hz, 1H), 3.23 (s,1H), 3.04 (d, J = 7.3 Hz, 3H), 2.44 (s, 2H), 2.25 (d, J = 11.9 Hz, 1H),2.11 (d, J = 12.7 Hz, 1H), 2.01-1.80 (m, 2H), 1.72 (d, J = 12.4 Hz, 2H),1.47 (s, 2H), 1.30 (t, J = 7.3 Hz, 5H). 982 A A 399.25 1.64 1H NMR (300MHz, MeOD) d 8.52 (s, 1H), 8.30 (d, J = 5.6 Hz, 3H), 4.50 (t, J = 12.1Hz, 1H), 3.48 (s, 2H), 3.35 (s, 2H), 3.04 (q, J = 7.3 Hz, 5H), 2.25 (d,J = 3.5 Hz, 4H), 2.02-1.82 (m, 2H), 1.70 (t, J = 12.5 Hz, 2H), 1.58-1.35(m, 3H), 1.30 (t, J = 7.3 Hz, 8H). 983 A A 486.2 1.83 984 A A 376.281.58 985 A A 439.24 1.94 986 A A 458.24 1.66 987 A A 401.83 2.12 988 A A401.9 1.99 989 B A 474.3 1.45 NMR 1H (MeOH-d4): 8.3 (m, 2H), 8.1 (s,1H), 4.4 (t, 1H), 3.8 (t, 1H), 3.6 (m, 4H), 3.4 (m, 4H), 2.3 (m, 1H),2.2 (m, 1H), 2.0 (m, 2H), 1.3- 1.7 (m, 4H). 990 A A 429.26 1.92 991 C C429.26 1.96 992 A A 526.3 1.99 in MeOH-d4 993 A A 438.21 1.83 994 A A512.3 1.83 NMR 1H (MeOH-d4): 8.6 (d, 1H), 8.4 (s, 1H), 8.3 (d, 1H), 8.2(m, 1H), 4.3 (t, 1H), 3.8 (t, 1H), 3.5-3.6 (m, 3H), 3.1 (m, 2H), 2.8 (t,1H), 2.3 (m, 3H), 2.2 (m, 2H), 2.0 (m, 2H), 1.85 (m, 1H), 1.3-1.75 (m,4H). 995 A A 470.5 2.04 1H NMR (300 MHz, DMSO) d 8.41 (dd, J = 9.8, 2.9Hz, 1H), 8.33-8.04 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 6.21 (d, J = 8.0Hz, 1H), 4.61 (s, 3H), 4.11 (d, J = 7.9 Hz, 1H), 3.90 (s, 3H), 3.66-3.42(m, 1H), 2.18-1.90 (m, 2H), 1.87- 1.69 (m, 2H), 1.58-0.68 (m, 8H) 996 AA 470.49 2.23 1H NMR (300 MHz, DMSO) d 8.41 (dd, J = 9.8, 2.9 Hz, 1H),8.32-8.04 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H),4.61 (s, 3H), 4.09 (s, 1H), 3.90 (s, 3H), 3.66-3.41 (m, 1H), 2.17-1.89(m, 2H), 1.78 (dd, J = 10.3, 7.1 Hz, 2H), 1.65-0.69 (m, 8H). 997 A A526.3 2 998 C C 526.3 2 999 A A 508.28 2.09 1000 A A 476.22 1.86 1001 AA 467.27 1.94 1002 A A 481.28 2.2 1003 A A 526.39 2.29 1004 A A 543.411.45 1005 A A 541.49 1.57 1006 A A 526.39 2.25 1007 A A 526.39 2.25 1008A A 429.45 2.64 CDCl3: 9.6 (m, 1H); 8.5 (dd, 1H); 8.25 (m, 2H); 8.1 (d,1H); 4.8 (appt, 1H); 4.5 (m, 1H); 3.4 (m, 1H); 2.8 (s, 3H); 2.6 (m, 1H);2.25 (m, 1H); 1.9 (m, 3H); 1.5-1.0 (m, 5H) 1009 A A 443.7 2.81 CDCl3:9.4 (m, 1H); 8.6 (dd, 1H); 8.25 (bs, 2H); 8.1 (d, 1H); 4.8 (appt, 1H);4.6 (m, 1H); 3.5 (m, 2H); 3.1 (m, 1H); 2.6 (m, 1H); 2.25 (m, 1H); 1.9(m, 3H); 1.5-1.0 (m, 6H) 1010 A A 487.29 1.93 CDCl3: 9.6 (m, 1H); 8.5(dd, 1H); 8.25 (bs, 2H); 8.0 (d, 1H); 4.75 (app t, 1H); 4.5 (m, 1H);4.25 (m, 1H); 3.6 (m, 1H); 3.55 (s, 3H); 3.5 (m, 2H); 2.7 (m, 1H); 2.26(app t, 1H); 2.0 (m, 3H); 1.9 (m, 3H); 1.5-1.0 (m, 7H) 1011 A A 473.281.79 1012 A C 504.06 2.09 1013 A A 486.47 2.52 1H NMR (d6-DMSO) 12.10(s, 1H), 8.48-8.45 (m, 1H), 8.40-8.32 (m, 3H), 6.12 (d, J = 7.8 Hz, 1H),4.27-4.09 (m, 2H), 3.72-3.47 (m, 1H), 3.41-3.11 (m, 2H), 2.17-1.98 (m,3H), 1.90- 1.72 (m, 4H), 1.60-1.37 (m, 2H), 1.32-1.20 (m, 1H) 1014 A A441.45 2.07 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.53-8.01 (m, 3H),7.89 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 4.33-3.68 (m, 4H), 2.74 (s, 2H),2.23 (d, J = 13.1 Hz, 1H), 2.08-1.73 (m, 3H), 1.70-1.08 (m, 3H). 1015 AA 527.47 1.38 1H NMR (300 MHz, DMSO) d 12.61 (s, 1H), 8.38 (ddd, J =9.6, 8.6, 2.9 Hz, 4H), 6.17 (d, J = 7.5 Hz, 1H), 4.20 (d, J = 10.5 Hz,1H), 3.91 (d, J = 30.8 Hz, 4H), 3.72-2.96 (m, 11H), 2.37- 1.68 (m, 6H),1.52-1.10 (m, 4H). 1016 A A 468.42 1.68 1H NMR (300 MHz, DMSO) d 12.67(s, 1H), 9.15 (s, 1H), 8.49 (dd, J = 9.3, 3.8 Hz, 3H), 8.28 (d, J = 2.0Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 4.32 (s, 1H), 3.67 (s, 1H), 3.57-3.46(m, 3H), 3.25-3.19 (m, 3H), 2.91-2.61 (m, 2H), 2.51 (dt, J = 3.6, 1.8Hz, 4H), 2.23-1.81 (m, 4H), 1.54-1.37 (m, 2H), 1.32-1.23 (m, 3H). 1017 AA 429.26 1.84 1018 A A 429.26 1.83 1019 A A 500.41 1.78 1020 A A 514.421.91 1021 A A 514.42 1.85 1022 A A 460.48 1.76 1H NMR (300 MHz, DMSO) d12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.29-8.20 (m, 2H), 8.14(d, J = 4.0 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 7.9 Hz, 1H),5.37 (s, 1H), 5.19 (s, 1H), 4.11 (d, J = 4.5 Hz, 1H), 3.63 (d, J = 7.6Hz, 1H), 3.57-3.40 (m, 2H), 3.23 (ddd, J = 18.1, 10.3, 5.4 Hz, 2H),2.17-2.01 (m, 3H), 1.90-1.74 (m, 2H), 1.52-1.20 (m, 4H). 1023 A A 499.452.15 H NMR (300.0 MHz, MeOD) d 8.51 (dd, J = 2.8, 9.6 Hz, 1H), 8.18-8.15(m, 2H), 7.99 (d, J = 4.1 Hz, 1H), 4.75 (s, H), 4.31-4.19 (m, H),3.82-3.73 (m, 2H), 3.76 (dd, J = 3.6, 11.9 Hz, 1H), 3.54-3.45 (m, 1H),2.68 (s, 3H), 2.36 (d, J = 11.8 Hz, 1H), 2.22-1.90 (m, 6H), 1.62 (s, H),1.52-1.24 (m, 4H) and −0.00 (TMS) ppm 1024 A A 427.27 2.07 1025 A A427.27 2.04 1026 A A 413.26 1.94 1027 B A 413.26 1.9 1028 A A 414.342.36 1H NMR (300 MHz, MeOD) d 8.56 (dd, J = 9.2, 2.8 Hz, 1H), 8.47 (s,1H), 8.37-8.32(m, 1H), 8.30 (d, J = 5.6 Hz, 1H), 5.17 (d, J = 6.9 Hz,1H), 3.69 (s, 3H), 2.96 (d, J = 6.8 Hz, 1H), 2.19-2.11 (m, 1H),2.09-2.02 (m, 1H), 1.74 (complex m, 9H). 1029 A A 443.27 1.97 CDCl3:9.75 (bs, 1H); 8.6 (dd, 1H); 8.25 (d, 1H); 8.23 (s, 1H); 8.15 (d, 1H);4.8 (d, 1H); 4.6 (m, 1H); 3.5 (m, 3H); 3.1 (m, 1H); 2.75 (bd, 1H); 2.25(bd, 1H); 2.0 (m, 2H); 1.4 (d, 3H); 1.25 (t, 3H). 1030 A A 443.27 1.99CDCl3: 9.75 (bs, 1H); 8.5 (dd, 1H); 8.25 (d, 1H); 8.23 (s, 1H); 8.0 (d,1H); 4.8 (d, 1H); 4.5 (m, 1H); 3.5 (m, 2H); 3.4 (m, 1H); 2.5 (bd, 1H);2.1 (bd, 1H); 1.7 (m, 3H); 1.4 (ddd, 1H); 1.2 (m, 6H). 1031 A A 416.461.69 1032 A A 510.52 2.1 1033 A A 479.39 2.08 1H NMR (300 MHz, DMSO) d12.23 (s, 1H), 8.50-8.46 (m, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H), 8.26(dd, J = 2.7, 1.5 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 4.0Hz, 1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H),7.31-7.15 (m, 2H), 6.32 (t, J = 5.8 Hz, 1H), 6.14 (d, J = 7.8 Hz, 1H),4.29 (d, J = 5.8 Hz, 2H), 4.22-3.97 (m, 1H), 3.57 (d, J = 7.7 Hz, 1H),2.21-2.10 (m, J = 11.0 Hz, 1H), 2.07- 1.98 (m, 1H), 1.95-1.72 (m, 2H),1.59-0.88 (m, 4H). 1034 A A 400.37 2.15 1H NMR (300 MHz, MeOD) d 8.58(dd, J = 9.3, 2.8 Hz, 1H), 8.41 (s, 1H), 8.29 (dd, J = 2.7, 1.7 Hz, 1H),8.22 (d, J = 5.3 Hz, 1H), 5.10 (d, J = 6.9 Hz, 1H), 2.89 (d, J = 7.0 Hz,1H), 2.17 (br s, 1H), 2.03 (br s, 1H), 1.99-1.49 (m, 7H). 1035 A A444.42 1.81 1036 A A 472.5 1.67 NMR 1H (MeOH-d4): 8.4 (m, 2H), 8.25 (m,2H), 4.4 (m, 1H), 3.8 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 2.35 (m, 1H),2.2 (m, 1H), 2.0 (m, 2H), 1.8 (m, 2H), 1.15-1.46 (6H). 1037 C C 470.41.72 1038 A A 470.4 1.73 1039 A A 458.43 1.61 H NMR (300.0 MHz, CDCl3) d7.70 (s, H), 7.28 (s, H), 7.11 (s, H), 5.31 (s, H), 4.17-4.02 (m, H),3.78 (s, H), 3.73 (q, J = 7.0 Hz, H), 3.49 (s, H), 2.97 (s, H), 2.90 (s,H), 2.65 (s, H), 2.03 (d, J = 11.7 Hz, H), 1.87 (s, H), 1.29- 1.21 (m,H) and 0.93 (d, J = 6.7 Hz, H) ppm 1040 A A 428.43 1.67 H NMR (300.0MHz, CDCl3) d 10.54 (s, H), 8.53 (dd, J = 2.8, 9.4 Hz, H), 8.50 (s, H),8.25- 8.06 (m, H), 7.30 (d, J = 10.7 Hz, H), 5.96 (s, H), 5.32 (s, H),4.95 (d, J = 8.0 Hz, H), 4.87 (d, J = 6.6 Hz, H), 4.27-4.11 (m, H),4.02-3.92 (m, H), 3.77 (t, J = 6.2 Hz, H), 3.51 (s, H), 2.92 (s, H),2.73-2.67 (m, H), 2.45-2.37 (m, H), 2.26 (d, J = 10.3 Hz, H), 2.18 (d, J= 3.9 Hz, H), 2.12 (s, H), 2.06-1.95 (m, H), 1.89 (s, H), 1.87 (q, J =3.4 Hz, H), 1.73 (d, J = 8.6 Hz, H), 1.67 (s, H), 1.63-1.58 (m, H),1.33-1.26 (m, H), 1.17 (t, J = 11.6 Hz, H), 0.94 (d, J = 6.6 Hz, H),0.85-0.68 (m, H), 0.61 (t, J = 7.0 Hz, H), 0.62 (s, H) and 0.53 (d, J =7.2 Hz, H) ppm 1041 A A 486.46 1.95 1H NMR (300 MHz, MeOD) d 8.42 (dd, J= 9.2, 2.8 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.34- 8.29 (m, 1H), 8.26(d, J = 5.5 Hz, 1H), 4.43 (dd, J = 14.0, 10.0 Hz, 1H), 3.99-3.90 (m,1H), 3.75 (ddd, J = 15.3, 7.6, 3.6 Hz, 2H), 3.40 (d, J = 5.3 Hz, 3H),3.35 (s, 3H), 2.36 (d, J = 11.9 Hz, 1H), 2.22 (d, J = 12.9 Hz, 1H),2.04- 1.75 (m, 7H), 1.68-1.19 (m, 6H). 1042 A C 457.5 1.31 1043 A A 1044A A 454.53 1.91 1045 A A 454.4 1.9 1046 C C 479.41 2.08 1H NMR (300 MHz,DMSO) d 12.23 (d, J = 2.3 Hz, 1H), 8.51-8.35 (m, J = 8.5, 4.9, 1.7 Hz,3H), 8.32-8.19 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.63 (dt, J = 7.8, 1.9Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.36-7.25 (m, 1H), 6.27 (t, J = 6.0Hz, 1H), 6.00 (d, J = 7.9 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 4.17-3.98(m, J = 10.5, 6.4 Hz, 1H), 3.67-3.44 (m, J = 7.8 Hz, 1H), 2.16 (d, J =11.3 Hz, 1H), 2.03 (d, J = 11.7 Hz, 1H), 1.95- 1.70 (m, J = 25.5, 11.7Hz, 2H), 1.53-0.93 (m, J = 33.7, 28.1, 12.8 Hz, 4H). 1047 A A 501.5 1.651048 A A 396.41 2.17 1H NMR (300 MHz, MeOD) d 9.07 (d, J = 6.8 Hz, 1H),8.56-8.50 (m, 2H), 8.37 (d, J = 5.6 Hz, 1H), 7.55 (dd, J = 8.1, 5.1 Hz,1H), 5.21 (d, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.00 (d, J = 6.6 Hz, 1H),2.21-2.15 (m, 1H), 2.10-2.05 (m, J = 5.8 Hz, 1H), 1.99-1.52 (m, 9H).1049 A A 440.62 2 1H NMR (300 MHz, MeOD) d 9.08 (d, J = 7.2 Hz, 1H),8.58 (s, 1H), 8.55 (dd, J = 5.3, 0.8 Hz, 0H), 8.34 (d, J = 5.6 Hz, 1H),7.74 (dd, J = 8.0, 5.4 Hz, 1H), 4.49-4.37 (m, 1H), 3.93-3.81 (m, 1H),3.67-3.56 (m, 4H), 3.39-3.31 (m, 4H), 2.42 (d, J = 11.1 Hz, 1H),2.17-2.05 (m, J = 11.4 Hz, 1H), 1.99 (burried m, 3H), 1.67- 1.26 (m,5H). 1050 A A 456.57 2.71 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.42(dd, J = 9.8, 2.8 Hz, 1H), 8.22 (ddd, J = 28.3, 14.1, 2.7 Hz, 3H), 7.49(d, J = 7.7 Hz, 1H), 5.79 (d, J = 7.9 Hz, 1H), 4.20-4.00 (m, 1H), 3.61(d, J = 8.0 Hz, 1H), 3.49-3.36 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H),2.84-2.65 (m, 1H), 2.22-1.72 (m, 5H), 1.48-1.10 (m, 5H), 0.98 (dd, J =6.6, 1.8 Hz, 3H). 1051 A A 456.44 2.6 1H NMR (300 MHz, DMSO) d 12.23 (d,J = 2.3 Hz, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.22 (ddd, J = 28.6,14.3, 2.8 Hz, 3H), 7.49 (d, J = 7.4 Hz, 1H), 5.79 (d, J = 7.9 Hz, 1H),4.21- 3.99 (m, 1H), 3.61 (d, J = 7.9 Hz, 1H), 3.40 (dd, J = 9.7, 7.3 Hz,1H), 3.14 (dd, J = 17.0, 7.6 Hz, 1H), 2.71 (dd, J = 9.7, 8.0 Hz, 1H),2.20-1.73 (m, 5H), 1.54-1.11 (m, 5H), 0.98 (d, J = 6.6 Hz, 3H). 1052 A A456.67 2.75 1H NMR (300 MHz, DMSO) d 12.23 (d, J = 2.1 Hz, 1H), 8.42(dd, J = 9.9, 2.9 Hz, 1H), 8.22 (ddd, J = 30.6, 15.3, 2.8 Hz, 3H), 7.49(d, J = 7.5 Hz, 1H), 5.74 (d, J = 7.9 Hz, 1H), 4.07 (d, J = 5.2 Hz, 1H),3.88 (dd, J = 8.7, 4.5 Hz, 1H), 3.69-3.50 (m, 1H), 3.27-3.24 (m, 1H),3.17 (t, J = 3.7 Hz, 1H), 2.21-1.66 (m, 5H), 1.38 (dd, J = 41.1, 29.2Hz, 5H), 1.04 (d, J = 6.2 Hz, 3H). 1053 A A 456.27 2.65 1H NMR (300 MHz,DMSO) d 12.23 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.22(ddd, J = 27.2, 13.6, 2.8 Hz, 3H), 7.49 (d, J = 7.5 Hz, 1H), 5.75 (d, J= 8.0 Hz, 1H), 4.26- 4.02 (m, 1H), 3.97-3.83 (m, 1H), 3.72-3.53 (m, 1H),3.31 (s, 1H), 3.16 (s, 1H), 2.15-1.64 (m, 5H), 1.44 (s, 5H), 1.04 (d, J= 6.2 Hz, 3H). 1054 A A 472.42 2.34 1H NMR (300 MHz, DMSO) d 12.27 (s,1H), 8.42 (dd, J = 9.9, 2.8 Hz, 1H), 8.27 (dd, J = 2.7, 1.4 Hz, 1H),8.23 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 7.5 Hz,1H), 7.29 (s, 1H), 6.70 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 4.11 (s, 1H),3.90 (d, J = 3.0 Hz, 1H), 3.62 (d, J = 8.1 Hz, 1H), 3.27 (d, J = 4.2 Hz,2H), 2.11 (d, J = 10.4 Hz, 1H), 1.99 (s, 2H), 1.93-1.77 (m, 4H), 1.75(s, 1H), 1.54-1.21 (m, 5H). 1055 A A 472.41 2.34 1056 A A 486.33 1.891057 A C 486.4 1.89 1058 A A 472.43 2.67 1H NMR (300 MHz, MeOD) d 8.46(dd, J = 10.0, 2.8 Hz, 1H), 8.17-7.91 (m, 2H), 4.28- 4.08 (m, 1H),3.88-3.71 (m, 1H), 3.62 (d, J = 5.1 Hz, 3H), 3.46-3.32 (m, 4H), 2.87 (s,3H), 2.32 (d, J = 11.9 Hz, 1H), 2.15 (d, J = 12.9 Hz, 1H), 2.03-1.85 (m,2H), 1.67-1.20 (m, 4H). 1059 A A 495 2.03 1060 A A 508 1.42 1061 A A 4741.89 NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.15-8.34 (m, 3H), 4.4 (m, 1H), 3.8(m, 1H), 3.5 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.9 (s, 1H), 2.4 (m,1H), 2.2 (m, 1H), 2.0 (m, 2H), 1.2-1.5 (m, 4H), 1.1 (t, 3H). 1062 A A458 1.68 1063 A A 444 1.91 1064 A A 504.5 1.91 H NMR (300.0 MHz, MeOD) d8.44 (dd, J = 2.8, 9.6 Hz, H), 8.14 (t, J = 4.5 Hz, H), 8.13 (s, H),7.98-7.94 (m, H), 7.70 (s, H), 7.06 (s, H), 6.28 (d, J = 7.3 Hz, H),5.49 (s, H), 4.83 (s, H), 4.52 (s, H), 4.22-4.09 (m, H), 3.75 (dd, J =3.8, 11.4 Hz, H), 3.69 (s, H), 3.57-3.30 (m, H), 3.26 (s, H), 3.10 (s,H), 2.99 (s, H), 2.87 (d, J = 8.6 Hz, H), 2.36-2.33 (m, H), 2.19 (d, J =12.2 Hz, H), 2.03 (d, J = 10.6 Hz, H), 1.95- 1.89 (m, H), 1.65 (s, H),1.61-1.52 (m, H), 1.43-1.13 (m, H) and −0.00 (s, H) ppm 1065 A A 4861.96 1066 A A 474 1.82 1067 A A 474 1.89 in MeOH-4 1068 A A 474 1.86 inMeOH-d4 1069 A A 484 1.99 1070 A A 400.39 2.15 1H NMR (300 MHz, MeOD) d8.66 (dd, J = 9.6, 2.8 Hz, 1H), 8.19 (s, 2H), 7.98 (d, J = 4.1 Hz, 1H),4.91 (d, J = 6.8 Hz, 1H), 2.75-2.63 (m, 1H), 2.18-1.41 (m, 10H). 1071 AA 400.56 2.15 1H NMR (300 MHz, MeOD) d 8.66 (dd, J = 9.6, 2.8 Hz, 1H),8.19 (s, 2H), 4.90 (d, J = 6.9 Hz, 1H), 2.75-2.64 (m, 1H), 2.15-1.42 (m,10H). 1072 A A 537 2.09 1H NMR (300 MHz, DMSO) d 12.55 (s, 1H), 8.40 (t,J = 3.1 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.33 (t, J = 3.7 Hz, 2H),6.43 (d, J = 7.7 Hz, 1H), 4.19 (d, J = 7.2 Hz, 1H), 3.66 (d, J = 7.4 Hz,1H), 3.48 (dd, J = 13.1, 5.9 Hz, 4H), 3.35-3.25 (m, 1H), 2.67 (d, J =7.0 Hz, 2H), 2.21-1.80 (m, 6H), 1.56-1.22 (m, 4H). 1073 A A 490 1.991074 A A 490 2.01 1075 A A 458 2.04 NMR 1H (MeOH-d4): 8.44 (s, 1H), 8.4(d, 1H), 8.3 (m, 1H), 8.2 (d, 1H), 4.3-4.4 (m, 2H), 3.8 (m, 1H), 3.2 (q,2H), 2.2-2.34 (m, 2H), 2.0 (m, 2H), 1.3-1.6 (m, 4H), 1.1 (m, 8H). 1076 AA 473 1.33 NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.4 (dd, 1H), 8.3 (m, 1H),8.26 (d, 1H), 4.4-4.45 (m, 1H), 3.8 (m, 1H), 3.5-3.7 (m, 2H), 3.3 (m,2H), 2.95 (m, 9H), 2.35 (m, 1H), 2.2 (m, 2H), 1.95 (m, 2H), 1.25-1.55(m, 5H). 1077 A A 474.43 1.68 H NMR (300.0 MHz, MeOD) d 8.47-8.25 (m,H), 7.98 (s, H), 4.95 (s, H), 4.89 (s, H), 4.82 (s, H), 4.49-4.40 (m,H), 4.21-4.10 (m, H), 4.01 (s, H), 3.92 (s, H), 3.54 (t, J = 1.7 Hz, H),3.44- 3.30 (m, H), 3.07 (t, J = 1.6 Hz, H), 2.99 (s, H), 2.87 (d, J =6.6 Hz, H), 2.65 (s, H), 2.51 (q, J = 12.1 Hz, H), 2.36-2.31 (m, H),2.24-2.04 (m, H), 1.99 (s, H), 1.81 (d, J = 11.6 Hz, H), 1.71-1.66 (m,H), 1.61-1.45 (m, H), 1.40- 1.37 (m, H), 1.18-1.08 (m, H), 0.19 (s, H),−0.00 (TMS) and −0.20 (s, H) ppm 1078 A A 481 1.91 NMR 1H (MeOH-d4): 8.5(s, 1H), 8.17-8.33 (m, 3H), 4.4 (m, 1H), 3.75 (m, 1H), 3.6 (m, 2H),2.7-2.9 (m, 3H), 2.4 (m, 1H), 2.2 (m, 1H), 2.05 (m, 2H), 1.2-1.7 (m,4H), 0.9 (m, 2H), 0.75 (m, 2H). 1079 A A 472.37 2.11 1H NMR (300 MHz,DMSO) d 12.23 (s, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.30-8.19 (m,2H), 8.13 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 5.77 (t, J =6.3 Hz, 1H), 4.66 (s, 1H), 4.20-4.04 (m, 1H), 3.71-3.50 (m, J = 7.7 Hz,1H), 3.30 (q, J = 5.3 Hz, 1H), 3.18 (dd, J = 7.8, 4.8 Hz, 2H), 3.04 (d,J = 10.5 Hz, 1H), 2.11 (d, J = 11.6 Hz, 1H), 2.00 (d, J = 9.5 Hz, 1H),1.88- 1.59 (m, 4H), 1.52-1.32 (m, 2H), 1.35-1.18 (m, 5H). 1080 A A 5002.01 NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.26-8.33 (m, 3H), 4.36 (m, 1H),4.05 (m, 1H), 3.9 (m, 1H), 3.75 (m, 2H), 3.3 (m, 2H), 3.2 (m, 2H), 2.4(m, 1H), 2.2 (m, 2H), 1.8-2.0 (m, 5H), 1.2-1.6 (m, 5H), 1.1 (t, 3H).1081 A A 512 1.84 NMR 1H (MeOH-d4): 8.4 (s, 1H), 8.25-8.35 (m, 3H), 4.7(s, 2H), 4.35 (m, 1H), 3.8 (m, 1H), 3.35 (q, 2H), 2.2-2.3 (m, 5H), 2.0(m, 2H), 1.3- 1.8 (m, 4H), 1.1 (t, 3H). 1082 B A 498.35 2.69 1H NMR (300MHz, CDCl3) d 10.71 (s, 1H), 8.53 (d, J = 9.9 Hz, 1H), 8.20 (s, 1H),8.11 (d, J = 2.9 Hz, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.29 (d, J = 6.9 Hz,1H), 4.14 (m, 1H), 3.82 (m, 4H), 3.34 (m, 4H), 2.56 (s, 1H), 2.30 (m,1H), 2.05 (m, 1H),, 1.91 (m 1H), 1.81-1.42 (m, 2H), 1.41-0.87 (m, 7H).1083 A A 456.2 2.74 1H NMR (300 MHz, MeOD) d 8.33-8.21 (m, 2H), 8.11(dd, J = 9.3, 2.3 Hz, 1H), 4.38 (m, 1H), 3.51(4 H), 3.72 (m, 1H), 2.85(s, 3H), 2.30 (m, 1H), 2.10 (m, 1H), 2.02-1.88 (m, 6H), 1.57-1.30 (m,4H). 1084 A A 486.46 1.76 1085 A A 458.5 2.05 1086 A A 444.61 1.87 1087A A 458.56 2.04 1088 C C 482.46 2.87 1H NMR (300 MHz, MeOD) d 8.40 (d, J= 10.0 Hz, 1H), 8.01 (dd, J = 17.7, 2.5 Hz, 2H), 4.14 (s, 1H), 3.84-3.53(m, 2H), 3.28 (s, 3H), 2.28 (d, J = 11.9 Hz, 1H), 2.11 (s, 1H),2.05-1.76 (m, 6H), 1.61-1.00 (m, 9H). 1089 A A 424.69 1.77 1H NMR (300MHz, MeOD) d 9.32-9.10 (m, 1H), 8.67 (s, 1H), 8.65-8.59 (m, 1H), 8.39(d, J = 5.6 Hz, 1H), 7.87 (dd, J = 8.1, 5.6 Hz, 1H), 4.53-4.34 (m, 1H),3.97-3.79 (m, 1H), 2.42 (d, J = 11.5 Hz, 1H), 2.11 (d, J = 10.5 Hz, 1H),2.05-1.83 (m, 5H), 1.70-1.33 (m, 4H). 1090 A A 382.61 1.96 1H NMR (300MHz, MeOD) d 9.00 (dd, J = 8.1, 1.5 Hz, 1H), 8.46 (dd, J = 5.0, 1.4 Hz,1H), 8.32 (d, J = 5.6 Hz, 1H), 7.47 (dd, J = 8.1, 5.0 Hz, 1H), 5.21-5.10(m, J = 6.8 Hz, 1H), 3.01- 2.87 (m, J = 6.8 Hz, 1H), 2.23-2.12 (m, 1H),2.06-1.98 (m, 1H), 1.98-1.47 (m, 7H). 1091 A A 472.25 1.77 1092 A A472.25 1.77 1093 A A 488.19 1.9 1094 A A 488.19 1.9 1095 A A 514.41 2.331H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.42 (dd, J = 9.8, 2.8 Hz, 1H),8.29-8.25 (m, J = 1.4 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.14 (d, J =4.0 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.23 (d, J = 7.7 Hz, 1H),4.21-3.92 (m, 3H), 3.60 (s, 1H), 3.17 (d, J = 5.2 Hz, 2H), 2.11 (d, J =12.4 Hz, 1H), 2.00 (d, J = 7.9 Hz, 1H), 1.81 (d, J = 10.7 Hz, 2H), 1.62(d, J = 11.8 Hz, 2H), 1.52-1.17 (m, 6H), 1.02 (d, J = 9.4 Hz, 8H). 1096A A 456.45 2.01 1097 A A 488 1.56 1098 A A 460.39 2.38 1H NMR (300 MHz,DMSO) d 12.27 (s, 1H), 8.42 (dd, J = 9.9, 2.8 Hz, 1H), 8.29-8.01 (m,3H), 7.50 (d, J = 7.1 Hz, 1H), 5.84 (d, J = 7.8 Hz, 1H), 5.60 (d, J =8.2 Hz, 1H), 4.29-3.99 (m, 1H), 3.72 (dd, J = 12.8, 6.6 Hz, 1H), 3.52(d, J = 8.1 Hz, 1H), 3.25-3.05 (m, 4H), 2.19- 1.68 (m, 3H), 1.52-1.11(m, 3H), 1.00 (d, J = 6.7 Hz, 3H). 1099 A A 470.35 2.2 1H NMR (300 MHz,DMSO) d 12.26 (d, J = 2.4 Hz, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.23(ddd, J = 30.4, 15.2, 2.7 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 6.14 (d, J= 8.0 Hz, 1H), 4.50 (d, J = 10.5 Hz, 2H), 4.25-3.95 (m, 1H), 3.62 (dd, J= 12.4, 6.7 Hz, 2H), 3.25-3.03 (m, 2H), 2.19- 0.90 (m, 10H). 1100 4741.55 1101 A A 502.5 1.76 1102 A A 571.14 1.65 1H NMR (300 MHz, DMSO) d12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.29-8.25 (m, J = 2.8,1.5 Hz, 1H), 8.23 (s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.54 (d, J = 7.7Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 4.20-4.08 (m, J = 5.2 Hz, 1H),4.08-3.98 (m, 2H), 3.97-3.86 (m, J = 11.5, 8.4 Hz, 1H), 3.30-3.23 (m,1H), 3.17 (d, J = 5.2 Hz, 1H), 3.07 (d, J = 5.4 Hz, 1H), 2.18- 2.07 (m,J = 11.8 Hz, 1H), 2.06-1.93 (m, J = 10.5 Hz, 1H), 1.92-1.74 (m, 6H),1.76-1.63 (m, 2H), 1.42 (dd, J = 23.4, 11.6 Hz, 2H), 1.35- 1.15 (m, 3H),0.81 (dd, J = 13.3, 6.8 Hz, 6H). 1103 A A 486 1.72 1H NMR (300 MHz,DMSO) d 8.36 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.20 (s,1H), 8.11 (d, J = 3.8 Hz, 1H), 7.43 (s, 1H), 6.13 (d, J = 7.5 Hz, 1H),5.76 (s, 1H), 4.13 (s, 2H), 3.24- 2.98 (m, 4H), 2.27-2.20 (m, 1H), 2.01(d, J = 11.5 Hz, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.63- 0.93 (m, 11H).1104 A A 490.43 1.59 1H NMR (300 MHz, d6-DMSO) δ 12.70 (s, 1H), 8.42 (s,1H), 8.34 (s, 1H), 8.26 (d, J = 17.1 Hz, 1H), 6.02 (d, J = 7.2 Hz, 1H),5.37 (s, 1H), 5.19 (s, 1H), 4.33 (s, 1H), 4.13 (s, 3H), 2.27 (s, 1H),2.10 (s, 3H), 1.77 (s, 5H), 1.48- 1.14 (m, 6H) 1105 A A 474.4 1.5 NMR 1H(MeOH-d4): 8.5 (s, 1H), 8.25-8.33 (m, 3H), 4.4 (m, 1H), 4.1 (d, 2H), 3.8(m, 1H), 3.5 (dd, 2H), 2.3-2.4 (m, 2H), 2.0 (d, 2H), 1.3- 1.6 (m, 4H).1106 A A 502.43 2.35 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J= 9.8, 2.8 Hz, 1H), 8.30-8.05 (m, 3H), 7.54 (d, J = 7.5 Hz, 1H), 5.96(d, J = 7.8 Hz, 1H), 4.26-3.93 (m, 1H), 3.80 (s, 2H), 3.59 (s, 1H),3.33-3.16 (m, 8H), 1.93 (dd, J = 67.2, 22.0 Hz, 4H), 1.60-0.89 (m, 5H).1107 A A 502.02 2.38 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J= 9.9, 2.8 Hz, 1H), 8.35-8.01 (m, 3H), 7.54 (d, J = 7.5 Hz, 1H), 5.96(d, J = 7.8 Hz, 1H), 4.13 (s, 1H), 3.80 (s, 2H), 3.69-3.44 (m, 1H), 3.28(d, J = 9.4 Hz, 7H), 2.04 (d, J = 32.3 Hz, 2H), 1.83 (d, J = 8.8 Hz,2H), 1.33 (dt, J = 25.0, 12.2 Hz, 5H). 1108 A A 516.71 2.2 1H NMR (300MHz, DMSO) d 12.26 (s, 1H), 8.65-7.90 (m, 4H), 7.53 (d, J = 6.6 Hz, 1H),6.29 (d, J = 6.9 Hz, 1H), 4.12 (s, 1H), 3.72- 2.94 (m, 11H), 2.04 (d, J= 30.8 Hz, 2H), 1.72 (d, J = 44.2 Hz, 3H), 1.32 (d, J = 56.3 Hz, 5H).1109 A A 516.41 2.39 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.27 (dd, J= 48.0, 38.1 Hz, 4H), 7.55 (s, 1H), 6.36 (s, 1H), 4.12 (s, 1H),3.81-2.81 (m, 11H), 2.21-1.68 (m, 5H), 1.32 (d, J = 53.8 Hz, 6H). 1110 AA 458.5 2.02 1111 A A 472.51 1.72 1112 A A 472.45 1.73 1113 A A 472.451.73 1114 A A 487.48 1.64 1115 A A 521.5 1.5 NMR 1H (MeOH-d4): 8.5 (s,1H), 8.3-8.35 (m, 3H), 6.37-6.7 (tt, 1H), 4.4 (m, 1H), 3.8 (m, 1H),3.5-3.75 (m, 5H), 2.18-2.4 (m, 2H), 2.0 (d, 2H), 1.3-1.7 (m, 4H). 1116 BC 445.45 1.64 1117 A A 501.56 2.16 1118 A A 486.5 1.68 NMR 1H (MeOH-d4):8.27-8.32 (m, 4H), 4.4 (m, 1H), 3.35 (m, 1H), 2.4-2.64 (m, 2H), 1.8- 2.2(m, 4H), 1.4-1.75 (m, 4H). 1119 A A 474.24 1.89 1120 A A 490.23 2.011121 A A 490.23 2.01 1122 A A 456.26 1.93 1123 A A 456.26 1.93 1124 A A472.25 2.06 1125 A A 472.19 2.06 1126 A A 474.24 1.89 1127 A A 492.082.82 1H NMR (300 MHz, DMSO) d 12.25 (s, 1H), 8.41 (dd, J = 9.8, 2.7 Hz,1H), 8.30-8.05 (m, 2H), 7.50 (s, 1H), 7.23 (td, J = 6.1, 2.9 Hz, 5H),6.17 (d, J = 8.3 Hz, 1H), 5.80 (d, J = 7.9 Hz, 1H), 4.73 (s, 1H), 4.11(d, J = 5.3 Hz, 1H), 3.50 (s, 1H), 2.21-1.66 (m, 4H), 1.28 (dd, J =14.7, 9.7 Hz, 7H). 1128 A A 458.41 2.87 1H NMR (300 MHz, DMSO) d 12.26(s, 1H), 8.42 (dd, J = 9.9, 2.9 Hz, 1H), 8.23 (ddd, J = 29.2, 15.1, 2.7Hz, 3H), 7.53 (d, J = 7.4 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 4.11 (d, J= 5.2 Hz, 1H), 3.62 (d, J = 7.8 Hz, 1H), 3.15 (dd, J = 9.6, 6.3 Hz, 2H),2.74 (s, 2H), 2.05 (dd, J = 27.0, 11.4 Hz, 2H), 1.81 (d, J = 11.2 Hz,2H), 1.55-1.06 (m, 7H), 0.86 (t, J = 7.2 Hz, 3H). 1129 A A 444.41 2.591H NMR (300 MHz, DMSO) d 12.26 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 9.8,2.8 Hz, 1H), 8.23 (ddd, J = 30.0, 15.0, 2.7 Hz, 3H), 7.53 (d, J = 7.5Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 4.35- 3.94 (m, 1H), 3.63 (d, J = 8.8Hz, 1H), 3.22- 3.02 (m, 2H), 2.75 (s, 2H), 2.05 (dd, J = 26.7, 11.8 Hz,2H), 1.81 (d, J = 10.5 Hz, 2H), 1.37 (ddd, J = 41.6, 24.7, 8.1 Hz, 6H),0.79 (t, J = 7.4 Hz, 3H). 1130 A A 444.1 2.6 1131 A A 430.07 2.47 1H NMR(300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.23(ddd, J = 29.8, 15.3, 2.7 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 6.00 (d, J= 7.9 Hz, 1H), 4.11 (d, J = 5.2 Hz, 1H), 3.62 (d, J = 9.3 Hz, 1H),3.25-3.06 (m, 2H), 2.74 (s, 2H), 2.05 (dd, J = 28.7, 11.2 Hz, 2H), 1.81(d, J = 10.5 Hz, 1H), 1.55-1.09 (m, 4H), 0.96 (t, J = 7.0 Hz, 2H). 1132A A 486.1 2.46 1H NMR (300 MHz, DMSO) d 12.26 (s, 1H), 8.42 (dd, J =9.8, 2.8 Hz, 1H), 8.20 (dd, J = 32.6, 8.6 Hz, 2H), 7.53 (d, J = 7.7 Hz,1H), 5.90 (d, J = 7.9 Hz, 1H), 4.28-3.92 (m, 2H), 3.62 (d, J = 7.1 Hz,1H), 3.45-3.08 (m, 9H), 2.21-1.68 (m, 5H), 1.53-0.89 (m, 6H). 1133 A A488.19 1.88 1H NMR (300 MHz, MeOD) d 8.36 (dd, J = 9.4, 2.6 Hz, 1H),8.28 (m, 2H), 5.13 (s, 2H), 4.35 (m, 1H), 3.79 (s, 1H), 3.67-3.56 (m,4H), 3.39-3.32 (m, 4H), 2.33 (m, 1H), 2.16 (m, 1H), 1.98 (m, 2H),1.69-1.20 (m, 4H). 1134 A A 442 2.3 NMR 1H (MeOH-d4): 8.5 (s, 1H), 8.3(m, 3H), 4.4 (m, 1H), 3.6 (m, 4H), 2.6 (m, 1H), 1.5-2.3 (m, 12H). 1135 AA 484.42 2.32 1H NMR (300 MHz, DMSO) d 12.23 (s, 1H), 8.42 (dd, J = 9.8,2.7 Hz, 1H), 8.33-8.06 (m, 3H), 7.49 (d, J = 7.7 Hz, 1H), 6.15 (d, J =7.7 Hz, 1H), 4.24 (s, 3H), 3.55 (d, J = 12.5 Hz, 3H), 2.83 (d, J = 12.5Hz, 2H), 1.99 (s, 2H), 1.72 (ddd, J = 33.2, 19.4, 9.2 Hz, 5H), 1.46-1.02 (m, 4H). 1136 A A 417.48 1.99 1137 A A 459.52 2 1138 A A 345.160.55 1H NMR (300 MHz, DMSO) d 12.40 (s, 1H), 8.56-8.13 (m, 2H), 7.89 (s,2H), 4.37 (s, 6H), 3.21 (d, J = 22.3 Hz, 1H), 2.27 (s, 1H), 2.01 (s,1H), 1.63-1.14 (m, 2H). 1139 A A 472.32 2.06 1H NMR (300 MHz, MeOD) d8.55 (dd, J = 9.8, 2.7 Hz, 1H), 8.08 (m, 2H), 5.12 (m, 2H), 4.19 (m,1H), 3.80 (m, 1H), 2.33 (m, 1H), 2.17 (m, 1H), 2.06-1.77 (m, 8H),1.69-1.21 (m, 4H). 1140 A A 443.53 2.29 1H NMR (300 MHz, CDCl₃) δ 9.91(s, 1H), 8.51 (dd, J = 9.4, 2.8 Hz, 1H), 8.26 (dd, J = 2.6, 1.7 Hz, 1H),8.22 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 3.5 Hz, 1H), 5.42 (d, J = 6.2 Hz,1H), 5.10-4.92 (m, J = 7.8, 3.9 Hz, 1H), 4.48- 4.30 (m, 1H), 3.42 (q, J= 11.8, 6.1 Hz, 4H), 2.44 (dt, J = 12.9 Hz, 1H), 2.11-1.81 (m, 7H),1.75-1.46 (m, 3H) 1141 A A 467.52 1.78 1142 A A 403.15 1.7 H NMR (300.0MHz, MeOD) d 8.67 (d, J = 2.3 Hz, 1H), 8.61 (s, 1H), 8.39 (d, J = 2.3Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 4.50-4.43 (m, 1H), 3.70-3.63 (m, 1H),3.31 (qn, J = 1.6 Hz, H), 2.47-2.39 (m, 1H), 2.30 (d, J = 12.1 Hz, 1H),2.15-2.08 (m, 2H), 1.70 (q, J = 11.9 Hz, 2H), 1.50-1.14 (m, 2H) and−0.00 (TMS) ppm 1143 A A 387.06 1.45 1144 A A 456.07 1.78 1H NMR (300MHz, MeOD) d 8.83 (s, 1H), 8.67-8.09 (m, 4H), 2.67 (s, 3H), 2.18 (dd, J= 101.0, 49.9 Hz, 5H), 1.34 (d, J = 29.6 Hz, 3H). 1145 A A 1H NMR (300MHz, DMSO) d 12.24 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 9.8, 2.9 Hz, 1H),8.26 (dd, J = 2.7, 1.5 Hz, 1H), 8.16 (d, J = 3.8 Hz, 1H), 7.78 (s, 1H),7.50 (d, J = 7.3 Hz, 1H), 4.58-4.18 (m, 1H), 3.42-3.32 (m, 1H), 2.11 (d,J = 13.1 Hz, 2H), 1.98-1.69 (m, 4H), 1.68- 1.14 (m, 4H), 0.92 (t, J =7.4 Hz, 3H). 1146 A A 1H NMR (300 MHz, DMSO) d 12.25 (d, J = 2.1 Hz,1H), 8.43 (dd, J = 9.8, 2.9 Hz, 1H), 8.26 (dd, J = 2.8, 1.5 Hz, 1H),8.21-8.10 (m, 2H), 7.80 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 4.59- 4.22(m, 1H), 3.33-3.20 (m, 4H), 2.31-1.96 (m, 2H), 1.94-1.16 (m, 7H), 0.92(t, J = 7.4 Hz, 3H). 1147 A A 1H NMR (300 MHz, DMSO) d 12.24 (s, 1H),8.39 (dd, J = 9.8, 2.8 Hz, 1H), 8.32-8.26 (m, 1H), 8.20 (dd, J = 9.7,3.2 Hz, 1H), 7.89 (s, 1H), 7.24 (t, J = 22.3 Hz, 1H), 4.37 (s, 1H), 3.47(d, J = 7.8 Hz, 1H), 2.18 (d, J = 10.5 Hz, 1H), 2.03-1.14 (m, 9H), 0.96(t, J = 7.3 Hz, 3H). 1148 A A 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H),8.39 (dd, J = 9.8, 2.9 Hz, 1H), 8.28 (dd, J = 2.7, 1.5 Hz, 1H), 8.18(dd, J = 4.9, 3.0 Hz, 1H), 7.92 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 4.32(s, 1H), 3.40 (d, J = 8.5 Hz, 1H), 2.14 (d, J = 12.7 Hz, 1H), 1.97-1.17(m, 9H), 1.10-0.80 (m, 3H). 1149 A A 445.51 2.37 1150 A A 457.47 2.471151 A A 461.51 2.15 1152 A A 493.5 2.39 1153 A A 443.21 1.99 1154 A A1H NMR (300 MHz, MeOD) d 8.63-8.40 (m, 1H), 8.31-8.03 (m, 2H), 7.99 (dd,J = 3.9, 1.1 Hz, 1H), 4.49 (t, J = 11.5 Hz, 1H), 3.44-3.25 (m, 3H),3.22-3.08 (m, 1H), 2.29 (dd, J = 40.0, 12.5 Hz, 2H), 2.13-1.16 (m, 8H),1.00 (q, J = 7.0 Hz, 3H). 1155 A A 457.28 2.16 1156 A A 457.28 2.13 1157A A 443.21 2.11 1158 A A 443.41 2.09 1H NMR (300 MHz, MeOD) d 8.63-8.40(m, 1H), 8.23-8.12 (m, 2H), 8.04 (t, J = 4.4 Hz, 1H), 4.56 (dd, J = 7.7,3.8 Hz, 1H), 3.64-3.47 (m, 1H), 2.28 (dd, J = 13.6, 4.0 Hz, 1H), 2.19-1.46 (m, 9H), 1.01-0.73 (m, 3H). 1159 A A 457.22 2.25 1160 A A 457.222.21 1161 A A 360.47 1.68 1162 A A 430.14 2.5 1H NMR (300 MHz, DMSO) d12.32 (s, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.17(dd, J = 4.8, 3.4 Hz, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.74 (t, J = 6.4Hz, 1H), 3.64 (d, J = 17.5 Hz, 3H), 2.95 (d, J = 6.9 Hz, 1H), 2.03- 1.30(m, 11H). 1163 C C 470.46 1.58 1164 A A 470.46 1.65 1165 A A 441.64 2.751H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.70-8.02 (m, 3H), 7.63 (dd, J =63.2, 7.4 Hz, 2H), 4.13 (s, 1H), 3.70 (s, 1H), 2.23-0.92 (m, 18H). 1166A A 455.65 2.96 1H NMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.62-7.97 (m,3H), 7.59 (dd, J = 41.7, 7.6 Hz, 2H), 4.13 (s, 1H), 3.71 (s, 1H),2.21-0.92 (m, 20H). 1167 C C 543.6 2.55 1168 A C 444.49 1.78 1169 A A486.52 1.74 1170 A A 531.57 2.02 1171 C A 577.51 2.57 1172 A A 501.52.16 1173 A A 442.29 2.94 1H NMR (300 MHz, DMSO) d 12.33 (d, J = 2.4 Hz,1H), 8.78 (dd, J = 19.9, 2.5 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.20 (d,J = 2.8 Hz, 1H), 8.13 (d, J = 4.1 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H),4.47-4.21 (m, 2H), 2.12 (s, 2H), 1.76- 1.33 (m, J = 25.6, 14.7 Hz, 11H),1.19 (d, J = 9.9 Hz, 3H), 1.08 (d, J = 7.0 Hz, 1H). 1174 C C 583.52 1.771H NMR (300 MHz, MeOD) d 8.49 (d, J = 6.1 Hz, 1H), 8.42 (d, J = 2.6 Hz,0H), 8.39 (s, 1H), 8.35 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H), 8.19 (d, J =4.1 Hz, 0H), 4.74-4.58 (m, 1H), 4.38 (dt, J = 42.8, 21.3 Hz, 2H), 3.84(dd, J = 16.3, 6.7 Hz, 1H), 3.70-3.58 (m, 1H), 3.48 (s, 1H), 3.31 (dt, J= 3.2, 1.6 Hz, 6H), 3.02 (s, 1H), 2.61 (t, J = 11.7 Hz, 1H), 2.21 (d, J= 6.0 Hz, 3H), 2.11- 1.86 (m, 5H), 1.86-1.27 (m, 7H), 0.92 (d, J = 6.1Hz, 6H). 1175 A A 456.35 2.98 1H NMR (300 MHz, DMSO) d 12.33 (s, 1H),8.83 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.8 Hz,1H), 8.13 (d, J = 4.1 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 4.33 (s, 1H),4.23-3.97 (m, J = 25.1, 15.2 Hz, 1H), 2.05 (bd s, J = 34.2 Hz, 2H),1.91-1.31 (m, 14H), 0.83 (t, J = 7.0 Hz, 3H). 1176 A A 401.17 1.72 1177A A 417.16 1.95 1H NMR (300 MHz, d6-DMSO) δ 12.39 (s, 1H), 8.74 (d, J =2.4 Hz, 1H), 8.55 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.4Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 4.51-4.31(m, 1H), 4.13-3.93 (m, 3H), 3.17 (d, J = 5.3 Hz, 1H), 2.11-1.89 (m, 1H),1.88-1.49 (m, 2H), 1.48-1.13 (m, 2H) 1178 A A 430.22 2.5 1H NMR (300MHz, DMSO) d 12.32 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.4Hz, 1H), 8.17 (dd, J = 4.9, 3.2 Hz, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.73(t, J = 6.3 Hz, 1H), 4.07 (q, J = 5.3 Hz, 2H), 3.61 (s, 3H), 3.17 (d, J= 5.3 Hz, 4H), 2.95 (d, J = 6.7 Hz, 1H), 2.02-1.35 (m, 10H). 1179 A A 1HNMR (300 MHz, DMSO) d 12.32 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.29 (d,J = 2.4 Hz, 1H), 8.24-8.11 (m, 2H), 7.60 (d, J = 6.9 Hz, 1H), 4.74 (t, J= 6.8 Hz, 1H), 4.07 (q, J = 5.3 Hz, 2H), 3.63 (s, 3H), 2.95 (d, J = 6.6Hz, 1H), 2.06-1.33 (m, 10H). 1180 A A 467.46 1.8 1181 A A 459.09 2.26 1HNMR (300 MHz, CDCl3) d 8.24 (s, 1H), 8.02 (d, J = 3.6 Hz, 1H), 4.36 (d,J = 6.8 Hz, 1H), 3.91 (s, 2H), 3.74-3.64 (m, 3H), 3.49- 3.30 (m, 3H),2.68 (s, 1H), 2.23 (s, 1H), 2.09 (s, 1H), 1.91 (s, 1H), 1.58 (d, J =13.4 Hz, 2H), 1.22 (dd, J = 21.2, 9.9 Hz, 3H). 1182 A A 486.65 2.05 1HNMR (300 MHz, DMSO) d 8.30-8.05 (m, 1H), 7.60 (dd, J = 7.3, 2.4 Hz, 1H),7.31 (dd, J = 5.0, 2.1 Hz, 1H), 4.09 (m, 1H), 3.57 (m, 1H), 3.17 (m,4H), 1.99 (m, 2H), 1.77 (m, Hz, 4H), 1.56-1.10 (m, 3H). 1183 A A 416.313.04 1H NMR (300 MHz, MeOD) d 8.94 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.2Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 4.1 Hz, 1H), 4.92 (d, J = 6.8 Hz,1H), 2.76 (d, J = 6.8 Hz, 1H), 2.07 (d, J = 23.8 Hz, 2H), 1.89-1.46 (m,7H). 1184 A A 416.13 2.26 1H NMR (300 MHz, MeOD) d 8.92 (d, 1H), 8.22(d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.02 (d, J = 4.2 Hz, 1H), 4.94 (d, J= 6.9 Hz, 1H), 2.78 (d, J = 6.7 Hz, 1H), 2.13-2.02 (m, 3H), 1.93- 1.45(m, 7H). 1185 A A 360.15 1.71 1186 A A 570.68 1.56 1187 A A 444.01 2.611H NMR (300 MHz, DMSO) d 12.74 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.58(s, 1H), 8.43- 8.34 (m, 2H), 4.94-4.84 (m, 1H), 4.08 (ddd, J = 7.1, 2.3Hz, 2H), 3.01 (d, J = 6.8 Hz, 1H), 2.05-1.99 (m, 1H), 1.98-1.84 (m, 2H),1.65 (complex m, J = 79.2 Hz, 8H), 1.13 (t, J = 7.1 Hz, 3H). 1188 A A396.24 1.97 1H NMR (300 MHz, MeOD) d 8.49 (ddd, J = 27.3, 9.7, 2.9 Hz,1H), 8.25-8.08 (m, 2H), 8.01 (dd, J = 9.2, 4.1 Hz, 1H), 7.73 (dd, J =23.6, 2.3 Hz, 1H), 7.56-7.43 (m, 1H), 6.28 (dt, J = 7.3, 2.4 Hz, 1H),4.73-4.27 (m, 2H), 2.60- 1.58 (m, 9H). 1189 C A 461 4.64 (400 MHz,DMSO-d6): 12.01 (b s, exchanged with D2O; 1H), 8.73 (d, J = 2 Hz; 1H),8.23 (d, J = 2 Hz; 1H), 8.10 (dd, J = 13.6, 4.4 Hz; 2H), 7.29 (bs,exchanged with D2O; 1H), 3.87-3.86 (m, 1H), 3.58-3.52 (m, 2H), 3.35-3.19(m, 2H), 2.07-1.95 (m, 2H), 1.88-1.70 1190 474.2 2.03 1191 476.15 2.341192 432.11 2.27 1193 A A 500.22 2.04 1H NMR (300 MHz, MeOD) d 8.45 (dd,J = 9.6, 2.7 Hz, 1H), 8.36-8.18 (m, 2H), 5.17 (t, J = 7.1 Hz, 1H), 4.42(m, 1H), 3.77 (m, 1H), 3.29 (m, 4H), 2.34-2.19 (m, 2H), 2.08-1.84 (m,4H), 1.74-1.28 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H). 1194 B A 500.28 2.231195 563.24 2.47 in DMSO-d6 and D20 exchange 1196 A A 388.43 1.84 1197 AA 415.18 1.96 1H NMR (300 MHz, MeOD) d 8.91 (d, J = 2.3 Hz, 1H), 8.44(s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 5.30 (d, J= 6.9 Hz, 1H), 2.86 (d, J = 6.8 Hz, 1H), 2.12-2.03 (m, 2H), 1.98-1.64(m, 6H), 1.63-1.52 (m, 2H). 1198 486.27 1.99 1199 486.43 2.14 1200 485.12.34 1201 458.98 2.18 1202 406.43 1.79 1H NMR (300 MHz, DMSO) d 12.08(s, 1H), 8.73 (ddd, J = 7.9, 4.4, 1.5 Hz, 1H), 8.41-7.98 (m, 3H), 7.47(dd, J = 41.7, 7.0 Hz, 1H), 7.19 (ddd, J = 14.2, 7.9, 4.7 Hz, 1H),5.82-5.63 (m, 2H), 4.71 (d, J = 73.1 Hz, 1H), 4.31 (d, J = 11.2 Hz, 1H),2.36-1.55 (m, 13H). 1203 490.23 1.99 1H NMR (300 MHz, CDCl3) d 11.09 (s,1H), 8.11 (s, 1H), 8.05 (m, 1H), 7.86 (d, J = 3.5 Hz, 1H), 5.32-4.78 (m,4H), 4.14 (d, J = 8.0 Hz, 1H), 3.84 (s, 1H), 3.74-3.18 (m, 6H), 2.67 (d,J = 11.7 Hz, 1H), 2.33-1.75 (m, 7H), 1.48- 1.27 (m, 2H), 1.26-0.95 (m,4H). 1204 457.06 2.04 1205 417.16 1.77 1206 429.58 1.94 1207 431.5 1.941208 429.5 1.85 1209 456.42 1.88 1210 472.47 1.75 1211 486.42 1.88 1212396.44 1.94 1H NMR (300 MHz, DMSO) d 12.28 (s, 1H), 8.59-8.07 (m, 4H),7.90-7.36 (m, 3H), 6.25 (dt, J = 16.0, 2.0 Hz, 1H), 4.79-4.15 (m, 2H),2.36 (d, J = 8.8 Hz, 1H), 2.19-1.55 (m, 6H), 1.50-1.10 (m, 1H). 1213480.65 2.16 1214 411.49 1.74 1215 460.23 1.91 1216 444.23 2.15 1217430.39 2.26 1H NMR (300 MHz, DMSO) d 12.38 (s, 1H), 8.75 (d, J = 2.4 Hz,1H), 8.55 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 3.8 Hz, 1H),8.22- 8.16 (m, J = 4.8 Hz, 2H), 7.47 (d, J = 31.1 Hz, 2H), 5.23 (t, J =8.1 Hz, 1H), 4.11 (q, J = 5.1 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 1.09(d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). 1218 406.18 1.8 1219406.44 1.79 1H NMR (300 MHz, DMSO) d 12.08 (s, 1H), 8.86-8.63 (m, 1H),8.39-7.90 (m, 3H), 7.53 (d, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.9, 4.7 Hz,1H), 5.74 (s, 1H), 4.27 (d, J = 10.5 Hz, 2H), 2.89 (s, 1H), 2.79-2.66(m, 1H), 2.15 (d, J = 48.2 Hz, 6H), 1.93-1.17 (m, 4H) 1220 424.44 2.1 1HNMR (300 MHz, DMSO) d 12.27 (s, 1H), 8.45 (dd, J = 9.8, 2.8 Hz, 1H),8.30-8.08 (m, 3H), 7.45 (d, J = 6.9 Hz, 1H), 4.86 (s, 1H), 4.59 (s, 1H),2.35-1.94 (m, 7H), 1.81 (d, J = 5.5 Hz, 5H). 1221 424.45 2.02 1222440.46 2.22 1223 440.5 2.34 1H NMR (300 MHz, DMSO) d 12.35 (s, 1H), 8.74(d, J = 2.4 Hz, 1H), 8.40-8.01 (m, 3H), 7.48 (d, J = 6.7 Hz, 1H), 4.84(s, 1H), 4.59 (s, 1H), 2.35-1.56 (m, 13H). 1224 461.19 2.46 1H NMR (300MHz, DMSO) d 12.56 (s, 1H), 8.72 (t, J = 8.2 Hz, 1H), 8.54 (t, J = 5.7Hz, 1H), 8.40 (t, J = 7.9 Hz, 1H), 8.33 (t, J = 3.4 Hz, 2H), 7.79 (d, J= 7.3 Hz, 1H), 4.66 (t, J = 8.0 Hz, 1H), 3.81 (qd, J = 17.5, 5.8 Hz,2H), 1.78 (td, J = 28.9, 16.0 Hz, 6H), 1.18 (s, 5H). 1225 517.24 2.99 1HNMR (300 MHz, DMSO) d 12.44 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.58 (d,J = 2.8 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 4.0 Hz, 1H),8.20 (s, 1H), 7.55 (s, 1H), 4.72 (t, J = 8.4 Hz, 1H), 4.17 (d, J = 9.2Hz, 1H), 1.90 (s, 2H), 1.68 (d, J = 21.4 Hz, 4H), 1.32-0.95 (m, 5H),0.84 (s, 9H). 1226 388.5 1.8 1227 510.23 2.12 1228 411.67 1.79 MeOD4;8.5 (dd, 1H); 8.26 (s, 1H); 8.25 (dd, 1H); 7.95 (d, 1H); 4.6 (app d,1H), 4.25 (m, 1H); 4.25 (m, 1H); 3.3 (m, 4H); 2.75 (m, 2H); 2.5 (app d,1H); 2.2 (m, 4H); 1.7 (m, 2H). 1229 416.42 2.29 H NMR (300.0 MHz, MeOD)d 8.72-8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.21 (d, J= 5.2 Hz, 1H), 4.71 (d, J = 6.3 Hz, 1H), 3.67-3.57 (m, 2H), 2.33-2.26(m, 1H), 2.10 (m, 1H), 1.78-1.70 (m, 1H), 1.28-1.25 (m, 7H) and 1.19 (s,3H) ppm 1230 A A 443.04 2.48 1H NMR (300 MHz, CDCl3) d 8.15 (d, J = 1.2Hz, 1H), 8.08 (d, J = 6.3 Hz, 1H), 7.88 (d, J = 3.3 Hz, 1H), 3.80 (d, J= 11.2 Hz, 1H), 3.68 (s, 1H), 3.26 (d, J = 6.4 Hz, 4H), 2.56 (d, J =11.8 Hz, 1H), 2.14 (d, J = 12.8 Hz, 1H), 1.99 (d, J = 10.3 Hz, 1H), 1.91231 A A 422.5 1.68 NMR 1H (MeOH-d4): 8.5 (dd, 1H), 8.15 (m, 2H), 8.0(d, 1H), 4.2 (m, 1H), 3.75 (m, 1H), 2.3 (d, 1H), 2.2 (d, 1H), 1.9 (m,2H), 1.2-1.6 (m, 4H). 1232 A A 450.5 1.8 NMR 1H (MeOH-d4): 8.2 (m, 4H),4.5 (m, 1H), 3.9 (m, 1H), 2.2 (m, 4H), 1.3-1.6 (m, 4H).

TABLE 4 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of FIG. 7 CellInfluenza Cell Flu, HA(-) 30 MDCK hr A/PR/8 protection, bDNA ATP (All:(All: IC50: EC50: Comp. uM)(Mean uM)(Mean LCMS_ LCMS_ Nos (All)) (All))Plus RT NMR 1300 D 334 1.8 1301 (400 MHz, CDCl3): 9.97 (br. s, exchangedwith D2O, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.18 (s, 1H),8.15 (d, J = 6.0 Hz, 1H), 6.21 (d, J = 4.8 Hz, 1H), 6.16 (br. s,exchanged with D2O, 1H), 3.45-3.35 (br. hump, 1H), 2.95-2.85 (br. hump,1H), 2.6-2.4 (br. hump, 3H), 1.98-1.7 (m, 4H), 1.59 (s, 3H), 1.57 (s,3H), 1.16 (d, J = 5.6 Hz, 3H) 1302 B (400 MHz, CDCl3): 9.95 (br. hump,exchanged with D2O, 1H), 8.95 (s, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.18(s, 1H), 8.14 (d, J = 6.0 Hz, 1H), 6.19 (d, J = 6.0 Hz, 1H), 5.72 (s,exchanged with D2O, 1H), 3.6-3.4 (m, 4H), 2.90-2.80 (m, 2H), 2.1-2.05(m, 2H), 1.52 (s, 6H) 1303 D 360 2.6 500 MHz, CDCl3: 10.8(br ex,1H),9.12(d,1H), 8.75(s,1H), 8.45(d,1H), 8.35(d,1H), 7.5(dd,1H), 7.31(d,1H),7.29(d,1H), 7.24(m,2H), 6.3(d,1H) 5.62(dt,1H), 2.9(m,2H), 2.23(dm,2H),2.0(m,2H) 1304 360 2.6 500 MHz, CDCl3: 10.8(br ex,1H), 9.12(d,1H),8.75(s,1H), 8.45(d,1H), 8.35(d,1H), 7.5(dd,1H), 7.31(d,1H), 7.29(d,1H),7.24(m,2H), 6.3(d,1H) 5.62(dt,1H), 2.9(m,2H), 2.23(dm,2H), 2.0(m,2H)1305 342 2.3 1306 342 2.3 500 MHz MeOD-d4: 8.65(d,1H), 8.42(s.1H),7.9(d,1H), 7.24(dd,2H), 7.13(m,4H), 6.5(d,1H), 5.65(m,1H), 2.8(m,3H),2.2(m,1H), 2.08(m,1H)1.9(m,3H) 1307 A A 380.2 3.52 DMSO d6 12.2 (s, 1H);8.7 (s, 1H); 8.3 (s, 1H); 8.15 (m, 2H); 7.0 (d, 1H); 5.4 (d, 1H); 4.8(d, 1H); 4.4 (bs, 1H); 4.1 (bs, 1H); 1.9-1.6 (m, 6H) 1308 370 2.1 500MHz: MeOD-d4: 8.9(d,1H), 8.4(s,2H), 8.3(d,1H), 7.4(m,1H), 2.1 (m,1H),1.9(m,2H), 1.8(m,2H), 1.75(m,2H), 1.3(m,6H) 1309 326 2.1 1310 327 0.4500 MHz, MeOD-d4: 8.75(dd,1H), 8.42(s,1H), 8.39(dd,1H),8.25(d,1H),7.69(d,2H), 7.35(dd,1H), 7.2(d,2H), 4.36(m,1H), 3.40(t,1H),3.2(m,1H),2.3(m,5H), 2.00(qin,1H), 1.7(m,4H) 1311 328.3 2 1312 A A 328.32 1313 D 330.1 2.25 (300 MHz, CDCl3) 10.68 (br s, 1H), 8.56 (dd, 1H),8.25 (d, 1H), 8.04 (d, 1H), 4.95 (d, 1H), 4.14 (m, 1 H), 2.20 (m, 2 H),1.89-1.31 (m, 7H) 1314 D 362 2.3 1315 B 360.2 3.05 (CDCl3, 300 MHz) 8.76(d, 1H), 8.28 (d, 1H), 7.99 (d, 1H), 7.98 (s, 1H), 4,92 (d, 1H),4.11 (m,1H), 3.89 (s, 3H), 2.21 (m, 2H), 1.89- 1.23 (m, 8H) 1316 D (400 MHz,CDCl3): 9.16 (s, exchanged with D2O, 1H), 9.07 (d , J = 2.0 Hz, 1H),8.30 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, addition of D2O changhedto s, 1H), 8.07 (d, J = 3.6 Hz, 1H), 5.28 (s, exchanged with D2O, 1H),2.98-2.95 (m, 1H), 1.05-1.00 (q, 2H), 0.75-0.71 (m, 2H). 1317 B (400MHz, CDCl3): 8.98 (s, exchanged with D2O, 1H), 8.92 (s, 1H), 8.28 (br.s, 1H), 8.17 (br. s, 1H), 7.98 (s, 1H), 4.42 (d, J = 6.4 Hz, addition ofD2O changed to s, 1H), 4.20- 4.15 (m, 1H), 2.25 (b r. d, J = 11.2 Hz,2H), 2.03 (s, 3H), 1.88 (br. d, J = 12.4 Hz, 2H), 1.78-1.75 (m, J = 13.2Hz, 1H), 1.61-1.50 (m, 2H), 1.33-1.27 (m, 3H). 1318 A A 312.1 1.96 H NMR(300 MHz, CDCl3) 10.72 (s, 1 H), 8.85 (dd, J = 1.3, 7.9 Hz, 1 H), 8.38(d, J = 3.9 Hz, 1 H), 8.25 (s, 1 H), 8.05 (d, J = 3.5 Hz, 1 H), 7.23(dd, J = 4.8, 8.0 Hz, 1 H), 4.97 (d, J = 6.5 Hz, 1 H), 4.23-4.13 (m, 1H), 2.22-2.18 (m, 2 H), 1.91-1.26 (m, 8 H) 1319 B 327.1 1.5 H NMR (300MHz, d4 methanol) 8.24 (d, 1H), 7.99 (s, 1H),1 7.92 (d, 1H), 7.88 (d,1H), 4.15 (m, 1H), 2.15 (m, 2 H), 1.91-1.26 (m, 8 H) 1320 D 360.2 2.31321 D 360.2 2.3 1322 D 374.2 2.4 1323 D 362.2 1.5 1324 D 328.2 2.07 HNMR (300 MHz, CDCl3) 10.84 (s, 1 H), 8.91 (d, J = 2.2 Hz, 1 H),8.29-8.14 (m, 3 H), 6.13 (d, J = 5.9 Hz, 1 H), 4.96 (s, 1 H), 3.86 (s, 1H), 2.15-1.48 (m, 10 H) 1325 D (400 MHz, DMSO-d6): 12.35 (br. s,exchanged with D2O, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz,additon of D2O changed to s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.16 (d, J =3.6 Hz, 1H), 7.84 (br. d, J = 6.4 Hz, exchanged with D2O, 1H), 4.64(sextet, J = 8.0 Hz, addition of D2O changed to quintet, J = 8.0 Hz,1H), 2.49-2.19 (m, 2H), 2.17- 2.10 (m, 2H), 1.80-1.72 (m, 2H). 1326 B(400 MHz, DMSO-d6): 12.31 (br. s, exchanged with D2O, 1H), 8.75 (br. d,J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H),8.13 (d, J = 3.6 Hz, 1H), 7.55-7.50 (m, exchanged with D2O, 1H),4.47-4.40 (m, 1H), 2.06-2.0 (m, 2H), 1.80-1.50 (m, 6H). 1327 D (400 MHz,DMSO-d6): 12.87 (d, J = 2.4 Hz, exchanged with D2O, 1H), 8.73 (d, J =2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.11(d,J = 2.4 Hz, addition of D2O changed to s, 1H), 6.70 (s,1H), 4.90 (br. s,exchanged with d20, 1H), 3.79 (s, 2H), 2.25-2.20 (m, 2H), 1.95-1.85 (m,2H), 1.80-1.62 (m, 4H). 1328 A A (400 MHz, DMSO-d6): 12.49 (s, exchangedwith D2O, 1H), 10.1 (s, exchanged with D2O, 1H), 8.72 (br. s, 1H), 8.29(br. s, 1H), 8.23-8.20 (m, 2H), 4.70-4.50 (m, 1H), 3.94 (br. s, 2H),2.69 (s, 3H), 2.32 (s, 2H), 2.19-2.00 (m, 6H). 1329 D 361.2 1.4 1330 D361.2 1.4 1331 D (400 MHz, DMSO-d6): 12.30 (s, exchanged with D2O, 1H),8.66 (d, J = 2.4 Hz, 1H), 8.40 (s, exchanged with D2O, 1H), 8.27 (d, J =2.4 Hz, 1H), 8.24 (d, J = 3.6 Hz, 1H), 8.03 (d, J = 2.8 Hz, 1H), 3.57(s, 3H),2.79-2.73 (m, 2H), 2.45-2.38 (m, 2H), 2.05- 1.96 (m, 2H). 1332 D(400 MHz, DMSO-d6): 13.11 (s, exchanged with D2O, 1H), 9.22 (s,exchanged with D2O, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 2.0 Hz,1H), 8.32 (s, exchanged with D2O, 2H), 8.07 (s, 1H), 4.20-4.17 (m,1H),3.15-3.10 (m, 1H), 2.16-2.10 (m, 7H), 1.70- 1.59 (m, 4H). 1333 D 3420.25 (d4-methanol, 300 MHz) 8.88 (d, 1H), 8.63 (s, 1H), 8.48 (d, 1H),8.36 (d, 1H), 3.89 (dd, 2H), 3.73-3.59 (m, 2H), 3.02 (dd, 2H), 2.44 (m,1H), 2.02 (br dd, 2H), 1.80 (m, 1H), 1.59 (m, 1H) 1334 D 377.1 3.863(400 MHz, DMSO-d6 + D2O): 8.64 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 8.39(d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 4.13-4.10 (m, 1H), 3.10-3.0 (m, 1H),2.10 (br. d, J = 10 Hz, 4H), 1.66-1.42 (m, 4H). 1335 D 406.1 3.217 (400MHz, DMSO-d6): 12.39 (s, exchanged with D2O, 1H), 8.74 (d, J = 2.0 Hz,1H), 8.34 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H),6.60 (s, exchanged with D2O, 1H), 2.25 (d, J = 13.2 Hz, 2H),1.95 (br. t,J = 11.6 Hz, 2H), 1.59-1.40 (m, 6H). 1336 D 396.1 5.16 (400 MHz,DMSO-d6): 8.66 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 8.26 (d,J = 2.0 Hz, 1H), 6.59 (d, J = 6.8 Hz, exchanged with D2O,1H), 4.27-4.20(m, 1H), 1.95 (br. s, 2H), 1.81 (br. s, 2H), 1.68(br. d, J = 11.2 Hz,2H), 1.54-1.42 (m, 4H). 1337 A A 411.2 1.166 (400 MHz, DMSO-d6 + D2O):8.67 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.06(s, 1H), 4.27-4.20 (br.s, 1H), 3.50- 3.40 (m, 1H), 2.10-1.50 (m, 8H).1338 D 376.2 2.13 NMR 1H DMSO-d6: 12.6 (s, 1H), 8.9 (s, 1H), 8.4 (m,3H), 8.0 (m, 1H), 4.8 (bs, 1H), 3.7 (s, 2H), 1.1-1.6 (m, 10H). 1339 D386.25 2.85 NMR 1H DMSO-d6: 12.7 (s,1H), 8.7 (m, 1H), 8.4 (m, 4H), 7.6(m, 2H), 5.5 (bs, 1H), 4.1 (m, 1H), 1.0-2.3 (m, 14H). 1340 A A 400.33.22 1341 B 355.4 3.1 1342 A A 428.2 2.84 1343 D 375.3 1.39(d4-methanol, 300 MHz) 8.83 (d, 1H), 8.44 and 8.29 (2s, 1H), 8.24 (d,1H), 8.18 (s, 1H), 8.05 (d, 1H), 3.72 (dd, 1H), 3.51 (m, 2 H), 2.84-2.64(m, 3 H), 2.77 (s, 3 H), 2.44 (m, 1 H), 2.15- 1.99 (m, 2 H), 1.79 (m, 1H), 1.36 (m, 1 H) 1344 A A 413.3 2.9 1345 A A 361.2 1.5 1346 D 361.2 0.71347 B 358.1 2.1 1348 D 313.2 2.15 1349 D 313.2 2 1350 D 313.2 2.08 1351B 327.2 2.15 1352 D 327.2 2.15 1353 A A 327.2 2.19 1354 B B 342.2 1.61355 D 313.6 1.04 1356 B 375.15 1.61 1357 A 347 1.3 1358 A A 363.3 1.31359 B 347.3 1.3 1360 D 367.3 1.4 1361 A 369.5 1.53 1362 C C 361.3 2.11363 A A 481.37 3.56 H NMR (300.0 MHz, MeOD) d 8.77 (d, J = 2.3 Hz, 1H),8.30 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H),7.58-7.54 (m, 5H), 4.94-4.87 (m, 1H), 4.45 (dd, J = 13.1, 30.3 Hz, 2H),3.78-3.54 (m, 2H), 3.47-3.37 (m, 1H), 2.46-2.40 (m, 1H) and 2.09 (m, 1H)ppm 1364 A C 348.11 3.46 1365 A A 362.33 3.29 H NMR (300.0 MHz, MeOD) d8.71 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.29(d, J = 5.5 Hz, 1H), 4.07 (s, 2H), 2.13 (qn, J = 1.5 Hz, H), 1.37-1.33(m, 2H) and 1.17-1.11 (m, 2H) ppm 1366 A A 362.15 3.6 Methanol d4 8.7(d, 1H); 8.2 (d, 1H); 8.1 (s, 1H); 8.0 (d, 1H); 7.65 (m, 1H);4.2 (m,2H); 2.0-1.6 (m, 6H) 1367 A A 1HNMR (400 MHz, DMSO- d6): 12.30 (s,exchanged with D2O, 1H), 9.17 (d, J = 2.4 Hz, 1H), 8.26(d, J = 2.4 Hz,1H), 8.22(d, J = 4 Hz, 1H), 8.17 (s,1H), 7.32(s, exchanged with D2O,1H), 3.32 (s,1H), 1.77-1.61(m,8H), 1.30-1.28 (m,2H) 1368 A A 1HNMR (400MHz, DMSO- vd6): 12.33(s, exchanged withD2O, 1H), 8.74 (d, J = 2.4 Hz,1H), 8.29(d, J = 2.4 Hz, 1H), 8 .17(d, J = 4 Hz, 1H), 8.10(d, J = 2 Hz,1H), 6.74(s,1H, partially exchanged with D2O), 4.60 (s, exchanged withD2O, 1H), 2.25(br s,2H), 2.12(br s, 5H), 1. 1369 A A 1HNMR (400 MHz,DMSO- d6): 12.33(s, exchanged with D2O, 1H), 8.70 (s, 1H), 8.28 (s, 1H),8.17(d, J = 4.4 Hz, 1 H), 6.99(s,1H), 4.3(s,1H), 2.20- 1.75(m,13H),1.55(d, J = 12.8 Hz,2H) 1370 A A 360.42 3.78 H NMR (300.0 MHz, DMSO) d12.35 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H),8.23-8.20 (m, 2H), 7.75 (d, J = 7.5 Hz, 1H), 4.45 (d, J = 9.4 Hz, 1H),2.65-2.62 (m, 2H), 2.50 (t, J = 1.8 Hz, H), 2.36 (dd, J = 12.2, 17.4 Hz,1H), 2.26-2.20 (m, 3H), 2.07-2.04 (m, 1H), 1.84- 1.74 (m, 2H) and −0.00(s, H) ppm 1371 A A (400 MHz, DMSO-d6): 12.32(s, 1H), 8.78(br s, 1H),8.28(br s,1H), 8.17(br s, 1H), 8.13(d, J = 3.6 Hz,1H), 7.40(d, J = 8 Hz,exchanged with D2O,1H), 4.85(br s, 1H), 2.31-2.25(m,1H),1.87-1.82(m,1H), 1.68(br s,2H),1.47(br s,1H), 1.29- 1.16(m,5H), 0.89-0.81(m,1H). 1372 A A (400 MHz, DMSO-d6): 12.33(s, 1H), 8.77(d, J = 2Hz,1H), 8.27(d,J = 2.4 Hz,1H),8.18(d, J = 2 Hz,1H), 8.13(d, J = 4Hz,1H),7.65(d, J = 8.4 Hz, 1H),4.85-4.77(m,1H), 2.64- 2. 60(m,1H),2.36-2.34(m,1H), 2.22- 2.19(m,1H),1.97(br s, 1H),1.85-1.84(m,1H),1.72- 0.83(m, 13H) 1373 A A (400 MHz, DMSO-d6): 12.51 (s, exchanged with D2O,1H),8.69 (s,1H), 8.32(d, J = 2 Hz,1H), 8.29(d, J = 3.6 Hz,1H), 8.23(s, 1H),6.96(s, exchanged with D2O, 1H), 3.03 (s, 2H), 2.47 (d, J = 12.8 Hz,2H),1.75-1.74(m,2H), 1.51(br s,5H), 1.35-1.33(m,1H). 1374 A A (400 MHz,DMSO-d6): 12.33(s, 1H), 8.77(d, J = 2 Hz, 1H), 8.27(d, J = 2.4 Hz, 1H),8.18(d, J = 3.2 Hz,1H), 8.13(d, J = 4 Hz,1H), 7.65(d, J = 8.4 Hz, 1H),4.83- 4.79(m,1H), 2.64- 2.19(m,3H), 1.97(br s,1H), 1.85-1.83(m,1H),1.72(dd,J1 = 11.6,6.4 Hz,1H), 1.28 (s,9H),1.1(d, J = 7,3H) 1375 B C360.4 3.82 H NMR (300.0 MHz, DMSO) d 12.53 (s, 1H), 8.63 (d, J = 2.4 Hz,1H), 8.33 (dd, J = 2.7, 9.8 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J = 3.2 Hz,1H), 2.65 (d, J = 10.3 Hz, 1H), 2.43-2.37 (m, 4H), 2.24 (t, J = 9.1 Hz,1H), 1.82 (t, J = 11.6 Hz, 2H) and −0.00 (s, H) ppm 1376 C C (400 MHz,DMSO-d6): 12.32 (s, exchanged with D2O, 1H), 8.76 (s, 1H), 8.29-8.11 (m,3H), 6.64 (s, exchanged with D2O, 1H), 2.25-2.14 (m, 9H), 1.80- 1.70 (m,6H). 1377 C C (400 MHz, DMSO-d6):12.35 (br s, 1H), 8.71(d,J = 2.4Hz,1H).8.29(d, J = 2.4 Hz.1H), 8.19- 8.17(m,2H), 6.79(d,J = 9.6 Hz,partially exchanged with D2O,1H),5.01-4.99(m, 1H),1.82-1.79(m,3H), 1.66-1.27(m,6H), 0.88(s,9H). 1378 A A 400 MHz, DMSO-d6): 12.32(s, 1H),8.74(d,J = 2 Hz,1H),8.28 (d,J = 2 Hz,1H), 8.18(d, J = 2.8 Hz, 1H),8.11(d,J = 3.6 Hz,1H),7.46(d, J = 8.8 Hz, 1H),4.19- 4.16(m,1H),1.99-1.91 (m,2H), 1.78-1.48(m,5H), 1.15-1.07(m,2H), 0.91(d,J = 6.8Hz,3H), 0.88(d,J = 7.2 Hz,3H), 0.71(d,J = 6.8 Hz,3H). 1379 A A 358.32.91 (400 MHz, DMSO-d6): 12.33 (br s,1H), 8.76 (d, J = 2 Hz,1H), 8.28(d,J = 2 Hz,1H), 8.18 (d, J = 2 Hz,1H), 8.14 (d, J = 3.6 Hz,1H), 7.6 (d,J = 5.6 Hz,1H) 4.37-4.36 (br m, 1H), 3.16 (d, J = 5.6 Hz,1H), 2.69 (brs, 1H), 2.24 (br s, 1H), 1.99 (t, J = 12,1H),1.6-1.2(m, 8H) 1380 A C403.34 3.1 1381 A C 388.37 4.04 1382 A A 388.37 4.02 1383 A 371.34 3.991384 C 388.37 4.26 1385 A A 388.37 4.26 1386 C C 401.23 3.89 1387 424.543.53 1H NMR (300 MHz, DMSO) d 12.30 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H),8.25 (d, J = 2.4 Hz, 1H), 8.32-8.09 (m, J = 19.6, 9.0 Hz, 2H), 7.62 (d,J = 7.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.77-6.59 (m, 2H), 4.57-4.33(m, 1H), 3.71 (s, 3H), 3.21-2.77 (m, 4H), 2.29-2.11 (m, J = 14.7 Hz,1H), 1.87-1.66 (m, J = 23.9, 12.0, 5.7 Hz, 1H).

TABLE 5 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of FIG. 8 Cell CellFlu, Influenza MDCK HA(-) 30 hr protection, A/PR/8 ATP (IC50: bDNA: bDNAIC50: EC50 Comp. uM)(Mean uM(Mean LCMS_ LCMS_ Nos (All)) (All)) Plus RTNMR 1400 B 361.44 3.7 1H NMR (DMSO-d6): 1.53 (3H, m), 1.81 (2H, m), 1.98(1H, m), 2.90 (1H, m), 3.31 (1H, m), 3.43 (1H, m), 3.58 (2H, m), 7.85(1H, s), 8.30 (2H, d), 8.36 (1H, s), 8.68 (1H, d), 8.84 (1H, s), 12.52(1H, s) 1401 B 361.44 3.59 1H NMR (DMSO-d6): 1.34 (1H, m), 1.60 (1H, m),1.92 (2H, m), 2.20 (1H, m), 2.78 (2H, m), 3.24 (3H, m), 3.54 (1H, m),7.99 (1H, s), 8.23 (1H, m), 8.30 (2H, d), 8.60 (1H, d), 8.70 (1H, s),12.45 (1H, s) 1402 D 361.44 3.57 1H NMR (DMSO-d6): 1.41 (2H, m), 1.92(2H, m), 2.08 (1H, m), 2.83 (2H, m), 3.29 (2H, m), 3.44 (2H, m), 7.97(1H, s), 8.20 (1H, s), 8.25 (1H, s), 8.30 (1H, s), 8.48 (1H, d), 8.71(1H, s), 12.43 (1H, s) 1403 B 347.4 3.67 1H NMR (DMSO-d6): 1.94 (1H, m),1.96 (2H, m), 2.14 (1H, m), 3.20 (2H, m), 3.71 (2H, m), 3.83 (1H, m),7.89 (1H, s), 8.30 (4H, m), 8.69 (1H, s), 8.91 (1H, s), 12.58 (1H, s)1404 347.4 3.54 1H NMR (DMSO-d6): 1.77 (1H, m), 2.12 (1H, m), 2.77 (1H,m), 3.00 (1H, m), 3.17 (1H, m), 3.34 (2H, m), 3.60 (2H, m), 7.98 (1H,s), 8.23 (1H, d), 8.31 (2H, m), 8.71 (3H, m), 12.53 (1H, s) 1405 D394.45 5.28 1H NMR (DMSO-d6): 2.04 (4H, m), 2.84 (2H, m), 3.33 (1H, s),5.61 (1H, m), 7.18 (3H, m), 7.27 (1H, d), 8.00 (1H, d), 8.21 (1H, t),8.23 (1H, s), 8.26 (1H, s), 8.68 (1H, s), 12.34 (1H, s) 1406 333 3.54 1HNMR (CD3OD): 2.40- 2.50 (2H, m), 2.6-2.7 (2H, m), 3.50-3.60 (3H, m),3.7- 3.8 (1H, m), 5.2-5.3 (1H, m), 8.40 (1H, s), 8.50 (1H, m), 8.55 (1H,s), 8.75 (1H, s) 1407 347 3.5 1H NMR (DMSO-d6): 1.80-1.90 (2H, m),2.1-2.2 (2H, m), 3.05-3.15 (2H, m), 3.4-3.5 (2H, m), 4.30-4.40 (1H, m),7.65-7.70 (1H, m), 8.30-8.35 (2H, m), 8.40- 8.50 (1H, s), 8.60-8.70 (1H,s), 8.75-8.80 (1H, m), 12.0 (1H, s) 1408 A 347.47 3.68 1H NMR (DMSO-d6):1.66 (1H, m), 1.85 (1H, m), 1.98 (1H, m), 2.11 (1H, m), 2.90 (2H, m),3.32 (1H, m), 3.47 (1H, m), 4.46 (1H, m), 7.57 (1H, d), 8.31 (3H, m),8.66 (3H, m), 12.47 (1H, s) 1409 D 348.44 4.42 1H NMR (DMSO-d6): 1.67(2H, m), 1.96 (2H, d), 3.49 (2H, t), 3.96 (2H, d), 4.30 (1H, m), 7.62(1H, d), 8.18 (1H, s), 8.22 (1H, s), 8.29 (1H, s), 8.72 (1H, s),12.36(1H, s) 1410 A 360.46 5.39 1H NMR (DMSO-d6): 1.17 (5H, m), 1.70 (6H, m),2.67 (2H, d), 8.27 (1H, s), 8.42 (2H, s), 8.72 (1H, s), 12.57 (1H, s)1411 374.5 5.47 1H NMR (DMSO-d6): 1.15 (8H, m), 1.28 (2H, m), 1.72 (2H,m), 1.84 (2H, m), 4.23 (1H, m), 7.43 (1H, d), 8.12 (1H, s), 8.18 (1H,s), 8.27 (1H, s), 8.73 (1H, s),12.32 (1H, s) 1412 A 346.43 5.25 1H NMR(DMSO-d6): 0.85 (1H, m), 1.48 (4H, m), 1.68 (1H, d), 1.81 (2H, m), 2.04(2H, m), 4.03 (1H, m), 7.49 (1H, d), 8.13 (1H, s), 8.19 (1H, s), 8.29(1H, s), 8.73 (1H, s), 12.21 (1H, s) 1413 362 4.5 (d6-DMSO, 400 MHz)1.23- 1.33 (2H, m), 1.72 (2H, d), 1.99-2.04 (1H, m), 3.27 (2H, t), 3.41(2H, t), 3.85- 3.89 (2H, m), 7.80 (1H, t), 8.14 (1H, d), 8.21 (1H, s),8.28 (1H, d), 8.74 (1H, d), 12.35 (1H, brs) 1414 375 3.95 (d6-DMSO, 400MHz) 1.14- 1.24 (2H, m), 1.75-1.80 (5H, m), 2.11 (3H, s), 2.75 (2H, d),3.40 (2H, t), 7.80 (1H, t), 8.13 (1H, d), 8.20 (1H, s), 8.28 (1H, d),8.73 (1H, d), 12.35 (1H, s) 1415 D 348 3.27 (d6-DMSO, 400 MHz) 1.66-1.74 (1H, m), 1.99-2.08 (1H, m), 2.67-2.74 (1H, m), 3.49-3.51 (2H, m),3.58-3.67 (2H, m), 3.73 (1H, t), 3.79-3.84 (1H, m), 7.88 (1H, t), 8.16(1H, d), 8.22 (1H, s), 8.29 (1H, d), 8.74 (1H, d), 12.36 (1H, brs) 1416B 347.47 3.54 1H NMR (CDCl3/MeOD): 0.83 (2H, m), 1.94 (1H, m), 2.32 (1H,m), 3.00 (1H, m), 3.30 (1H, m), 3.36 (2H, m), 3.46 (1H, m), 3.60 (1H,m), 3.87 (1H, m), 8.15 (1H, s), 8.24 (1H, s), 8.29 (1H, s), 8.68 (1H, s)1417 D 333.51 5 1H NMR (DMSO-d6): 2.15 (1H, m), 2.30 (2H, m), 3.35 (2H,m), 3.58 (1H, m), 4.77 (1H, m), 7.87 (1H, s), 8.29 (3H, m), 8.81 (1H,s), 8.94 (2H, br s), 12.45 (1H, s) 1418 D 333.4 5 1H NMR (DMSO-d6): 2.17(1H, m), 2.34 (1H, m), 3.34 (3H, m), 3.58 (1H, m), 4.79 (1H, m), 7.87(1H, d), 8.27 (3H, m), 8.68 (1H, s), 8.81 (2H, br s), 12.45 (1H, s) 1419B 403.48 3.18 1H NMR (DMSO-d6): 0.82 (2H, m), 1.11 (1H, m), 1.22 (1H,m), 1.85 (2H, t), 1.98 (3H, s), 2.07 (1H, br s), 3.00 (1H, t), 3.51 (1H,s), 3.83 (1H, m), 4.40 (1H, d), 8.40 (1H, s), 8.44 (1H, d), 8.65 (1H,s), 8.88 (1H, s), 9.20 (1H, br s), 12.91 (1H, s)

In Vivo Assay

For efficacy studies, Balb/c mice (4-5 weeks of age) were challengedwith 5×10³ TCID₅₀ in a total volume of 50 μl by intranasal by intranasalinstillation (25 μl/nostril) under general anesthesia(Ketamine/Xylazine). Uninfected controls were challenged with tissueculture media (DMEM, 50 μl total volume). For the prophylaxis study(FIG. 1), the initial dose of Compound 514 (100 mg/kg) or vehicle only(0.5% Methylcellulose/0.5% Tween 80) were administered 2 hours prior toinfection by oral gavage (10 mL/kg) and continued twice daily for 5days. For the treatment study (FIG. 2), Compound 588 (200 mg/kg) orvehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered byoral gavage 24 hours post infection and continued twice daily for 10days. Animals were monitored for survival for 21 days and Kaplan Meierplots. As shown in FIGS. 1 and 2, Compound 514 and Compound 588 providedcomplete survival that was statistically significant from vehicletreated controls (P<0.0001).

TABLE 6 Influneza Therapeutic Mouse Model (Dosing @ 48 hours postinfection with 30 mg/kg BID × 10 days) Compounds Percent SurvivalPercent Weight Loss (Day 8) 895 100 12.8 936 100 20.9 933 100 28.0 70675 27.0 967 75 30.9 866 62.5 29.5 968 37.5 32.7

All references provided herein are incorporated herein in its entiretyby reference.

As used herein, all abbreviations, symbols and conventions areconsistent with those used in the contemporary scientific literature.See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authorsand Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1-156 (canceled)
 157. A method of inhibiting the replication or reducingthe number of influenza viruses in a biological sample or in a patientcomprising administering to said biological sample or patient aneffective amount of a compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein: Z¹ is —R*, —F,—Cl, —CN, —OR*, —CO₂R*, —NO₂, or CON(R*)₂; Z² is —R*, —OR*, —CO₂R*,——NR*₂, or CON(R*)₂; Z³ is —H, —OH, halogen, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl), or C₁-C₆ alkyl that is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); R¹is —H, C₁-C₆ alkyl, S(O)₂-R″, or —C(O)OR″; R² is —H, —F, —NH₂, —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)₂, C═N—OH; cyclopropyl that is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, —OCH₃, and —CH₃; orC₁-C₄ alkyl that is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁-C₄ alkyl); R³ is —H, —Cl, —F, —Br, —OH, —O(C₁-C₄alkyl), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —CN, or C₁-C₄aliphatic that is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; R⁴is:

wherein: ring E is a C₄C₈ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A); ring F is a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(E1); each of rings G1 and G2 is independently a5-10 membered non-aromatic bridged carbocycle optionally substitutedwith one or more instances of J^(A); each J^(A) is independentlyselected from the group consisting of halogen, cyano, oxo, —NCO, andQ¹-R⁵; or optionally two J^(A), together with the atom(s) to which theyare attached, independently form a 4-8 membered ring that is optionallysubstituted with one or more instances of J^(E1); Q¹ is independently abond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂—, —OC(O)—, —C(O)NR—,—C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂—,—OC(O)NR—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂NR′—, —NRSO₂NR′—, or—(CR⁶R⁷)_(p)—Y¹—; Q² is independently —O—, —CO₂—, —OC(O)—, —C(O)NR—,—NRC(O)—, —NRC(O)NR—, —NRCO₂—, —OC(O)NR—, —CO₂SO₂—, —P(O)₂O—, or—(CR⁶R⁷)_(p)—Y¹—; Y¹ is independently —O—, —CO₂—, —OC(O)—, —C(O)NR—,—NRC(O)—, —NRC(O)NR—, —NRCO₂—, or —OC(O)NR—; R⁵ is: i) —H, ii) anoptionally substituted C₁-C₆ alkyl group, iii) an optionally substitutedC₃-C₇ non-aromatic carbocycle, iv) an optionally substituted 4-7membered non-aromatic heterocycle, or optionally, together with R andthe nitrogen atom to which R is attached, form a 5-7 membered,optionally substituted non-aromatic heterocycle, wherein the alkyl grouprepresented by R⁵ is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₁ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, an optionally substituted C₃-C₇ non-aromatic carbocycle, and anoptionally substituted 4-7 membered non-aromatic heterocycle; whereineach of said carbocycles and heterocycles represented by R⁵ isindependently and optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄alkyl) and —CO₂H, wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; each of R⁸ and R⁹ isindependently -—H, halogen, cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄ alkoxyalkyl, —O(C₁-C₄ alkyl), —NH₂,—NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂; R¹¹, R¹², R¹³ and R¹⁴ are eachindependently —H, halogen, or C₁-C₆ alkyl optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or optionally, R¹³ and R¹⁴,together with the carbon atom to which they are attached, form acyclopropane ring, optionally substituted with one or more instances ofmethyl; R²¹, R²², R²³ and R²⁴ are each independently —H, halogen, —OH,or C₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; R⁶ and R⁷ are each independently —H or C₁C₆ alkyloptionally substituted with one or more substitutents selected from thegroup consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy, or optionally R⁶ and R⁷, togetherwith the carbon atom to which they are attached, form a cyclopropanering optionally substituted with one or more instances of methyl; R andR′ are each independently —H or C₁-C₆ alkyl optionally and independentlysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; or optionally R′, togetherwith R⁵ and the nitrogen atom to which they are attached, form a 5-7membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(D1); each J^(D1) is independently selected from thegroup consisting of halogen, cyano, oxo, —R^(a), —OR^(b), —SR^(b),—SOR^(a), —SO₂R^(a), —NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b),—NHC(O)R^(b), —(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), —NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and 13 N(CH₃)SO₂R^(b); R″ is independently: i) aC₁-C₆-alkyl optionally substituted with one or more substituentsselected independently from the group consisting of halogen, cyano,hydroxyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy; or ii) a C₃-C₆ carbocyclic group, a 5-6 memberedheteroaryl group, or a phenyl group, each optionally and independentlybeing substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, nitro, —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆cyanoalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkoxyalkyl, C₁-C₆-aminoalkyl,C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy,C₁-C₆-hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; R* is independently: i)—H;ii) a C₁-C₆ alkyl group optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₃-C₈ non-aromaticcarbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 memberedheteroaryl, —O(C₁-C₆ alkyl), and —C(O)(C₁-C₆-alkyl); wherein each ofsaid alkyl groups in —O(C₁-C₆ alkyl), and —C(O)(C₁-C₆-alkyl) isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁C₄ alkyl), and C_(I)C_(a)alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, andheteroaryl is independently and optionally substituted with one or moreinstances of J^(E1); or iii) a C₃-C₈ non-aromatic carbocycle, or a 4-8membered non-aromatic heterocycle, each of which is independently andoptionally substituted with one or more instances of J^(E1); each J^(E1)is independently selected from the group consisting of halogen, cyano,hydroxy, oxo, amino, carboxy, amido, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and—C(O)(C₁-C₆-alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), CO(CIC₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; each R^(a) isindependently: i) a C₁-C₆ aliphatic group optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido,—O(C₁-C₆ alkyl), —C(O)(C₁-C₆-alkyl), C₃-C₈ non-aromatic carbocycle, 4-8membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and6-10 membered carbocyclic aryl group; wherein each of said alkyl groupsfor the substituents of the C₁-C₆ aliphatic group represented by R^(a)is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl,and carbocyclic aryl groups for the substituents of the C₁-C₆ aliphaticgroup represented by Ra is optionally and independently substituted withone or more instances of J^(E1); ii) a C₃-C₈ non-aromatic carbocycle, ora 4-8 membered non-aromatic heterocycle, each of which is optionally andindependently substituted with one or more instances of J^(E1); or iii)a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group,each of which is optionally and independently substituted with one ormore instances of J^(E1); R^(b) and R^(c) are each independently R^(a)or —H; or optionally, R^(b) and R^(c), together with the nitrogenatom(s) to which they are attached, each independently form a 5-7membered non- aromatic heterocycle optionally substituted with one ormore instances of J^(E1); p and q are each independently 0, 1 or 2; x is0, 1 or 2; and r is 1 or
 2. 158. The method of claim 157, wherein R⁴ is:

wherein: ring E is a C₄-C₈ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A); ring F is a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(E1); R⁹ is independently -—H, halogen, cyano,hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄alkoxyalkyl, —O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄alkyl)₂; R¹¹, R¹², R¹³ and R¹⁴ are each independently —H, halogen, orC₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; or optionally, R¹³ and R¹⁴, together with the carbon atomto which they are attached, form a cyclopropane ring, optionallysubstituted with one or more instances of methyl; p is 0, 1 or 2; and xis 0, 1 or
 2. 159. The method of claim 158, wherein ring F is selectedfrom any one of rings F1-F6:

wherein each of rings F1-F6 is optionally and independently substitutedwith one or more instances of J^(E1); and each R^(f) is independently —Hor C₁-C₆ alkyl optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆cyanoalkoxy, and C₁-C₆ hydroxyalkoxy.
 160. The methodof claim 157, wherein R⁴ is:


161. The method of claim 160, wherein Q² is independently —O—, —CO₂—,—OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO₂—, —OC(O)NR—, or—(CR⁶R⁷)_(p)—Y¹—.
 162. The method of claim 161, wherein Q² isindependently —O—or —O₂—.
 163. The method of claim 160, wherein: R⁵ isindependently i) —H; ii) an optionally substituted C₁-C₆ alkyl group;iii) an optionally substituted C₃-C₇ non-aromatic carbocycle; or iv) a4-7 membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(D1).
 164. The method of claim 160, wherein: R¹ is—H; R² is —H, —CH₃, —CH₂OH, or —NH₂; R³ is —H, —F, —Cl, C₁-C₄ alkyl, orC₁-C₄ haloalkyl; Z¹ is —H, —F, or —Cl; Z² is —H or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, and—O(C₁-C₄ alkyl); Z³ is —H or C₁-C₆ alkyl optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); R⁵ is: i) —H; ii) anoptionally substituted C₁-C₆ alkyl group; iii) an optionally substitutedC₃-C₇ non-aromatic carbocycle; or iv) an optionally substituted 4-7membered non-aromatic heterocycle; or optionally, together with R andthe nitrogen atom to which it is attached, form a 5-7 membered,optionally substituted non-aromatic heterocycle; and said alkyl grouprepresented by R⁵ is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, an optionally substituted C₃-C₇ non-aromatic carbocycle , anoptionally substituted 4-7 membered non-aromatic heterocycle ; andwherein each of said carbocycles and heterocycles represented by R⁵, andreferred to for the substituents of the C₁-C₆ alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁-C₄ alkyl) and —CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —O(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.
 165. The compound of claim 165, wherein: R¹ is —H; R² is —H or—CH₂OH; R³ is —H, —F, or —Cl; Z¹ is —H, —F, or —Cl; Z² is —H; Z³ is —H;R⁵ is independently: i) —H or ii) a C₁-C₆-alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁C₄ alkyl,—O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —(O)O(C₁-C₄ alkyl), —CO₂H, —C₃-C₇non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl,and 5-6 membered heteroaryl; wherein each of said alkyl groups referredto in the substituents of the C₁-C₆ alkyl group represented by R⁵ isindependently and optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy;and wherein each of said carbocycle, phenyl, heterocycle, and heteroarylreferred to in the substituents of the C₁-C₆ alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and —C₁-C₄ alkoxy.
 166. The method of claim 160, wherein each ofJ^(A) is selected from the group consisting of halogen, cyano, hydroxy,C₁-C₆ alkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,—C(O)(C₁-C₄-alkyl), —OC(O)(C₁-C₄ alkyl), —NHC(O)(C₁-C₄ alkyl), and—N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl); wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.167. The method of claim 166, wherein each of J^(A) is selected from thegroup consisting of halogen, cyano, hydroxy, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), C₁-C₄ alkoxy, and CIC₄ alkyl optionally substituted with one ormore substituents selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁-C₄ alkyl).
 168. The method of claim 160, wherein: R¹is —; R² is —H; R³ is —H, —F, or —Cl; Z¹ is —H, —F, or —Cl; Z² is —H; Z³is —H; R⁵ is —H, or an optionally substituted C₁-C₆ alkyl; each R⁸ isindependently —H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —O(C₁-C₄ alkyl); each of R⁹, R¹³,and R¹⁴ is independently —H or C₁-C₄ alkyl; R²¹, R²², R²³, an R²⁴ areeach independently —H, halogen, —OH, or C₁-C₆ alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, and —O(C₁-C₆ alkyl); and eachof rings G1-G2 is independently a 5-10 membered non-aromatic bridgedcarbocycle optionally substituted with one or more substituents selectedfrom the group consisting of halogen, cyano, hydroxy, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), C₁-C₄ alkyl that isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, hydroxy, and C₁-C₄ alkoxy.
 169. The methodof claim 160, wherein x is 0 or
 1. 170. The method of claim 160, whereinR³ is methyl or ethyl.
 171. The method of claim 157, wherein thecompound of Formula (IA) is selected from

or a pharmaceutically acceptable salt thereof.
 172. A method of treatinginfluenza infection in a patient comprising administering to saidpatient an effective amount of a compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein: Z¹ is —R*, —F,—Cl, —CN, —OR*, —CO₂R*, —NO₂, or —CON(R*)₂; Z² is —R*, —OR*, —CO₂R*,—NR*₂, or —CON(R*)₂; Z³ is —H, —OH, halogen, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl), or C₁-C₆ alkyl that is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); R¹is —H, C₁-C₆ alkyl, —S(O)₂-R″, or —C(O)OR″; R² is —H, —F, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, C═N—OH; cyclopropyl that isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, —OCH₃,and —CH₃; or —C₁-C₄ alkyl that is optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); R³ is —H, —CI, —F, —Br,—OH, —O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —CN, orC₁-C₄ aliphatic that is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-Ca alkyl), CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; R⁴ is:

wherein: ring E is a C₄-C₈ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A); ring F is a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(E1); each of rings G1 and G2 is independently a5-10 membered non-aromatic bridged carbocycle optionally substitutedwith one or more instances of J^(A); each J^(A) is independentlyselected from the group consisting of halogen, cyano, oxo, —NCO, andQ¹-R⁵; or optionally two J^(A), together with the atom(s) to which theyare attached, independently form a 4-8 membered ring that is optionallysubstituted with one or more instances of J^(E1); Q¹ is independently abond, —O—, —S—, —NR—, —C(O)—, —C(═NR)—, —CO₂—, —OC(O)—, —C(O)NR—,—C(O)NRC(O)O—, —NRC(O)NRC(O)O—, —NRC(O)—, —NRC(O)NR—, —NRCO₂, —OC(O)NR—,—S(O)—, —SO₂—, —N(R)SO₂—, —SO₂NR′—, —NRSO₂NR′—, or —(CR⁶R⁷)_(p)—Y¹—; Q²is independently —O—, —CO₂—, —OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—,—NRCO₂—, —OC(O)NR—, —CO₂SO₂—, —P(O)₂O—, or —(CR⁶R⁷)_(p)—Y¹—; Y¹ isindependently —O—, —CO₂—, —OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—,—NRCO₂—, or —OC(O)NR—; R⁵ is: i) —H, ii) an optionally substituted C₁-C₆alkyl group, iii) an optionally substituted C₃-C₇ non-aromaticcarbocycle, iv) an optionally substituted 4-7 membered non-aromaticheterocycle, or optionally, together with R and the nitrogen atom towhich R is attached, form a 5-7 membered, optionally substitutednon-aromatic heterocycle, wherein the alkyl group represented by R⁵ isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄ alkoxy, an optionallysubstituted C₃-C₇ non-aromatic carbocycle, and an optionally substituted4-7 membered non-aromatic heterocycle; wherein each of said carbocyclesand heterocycles represented by R⁵ is independently and optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₄-C₄ alkyl,—O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl) and CO₂H, wherein eachof said alkyl groups is optionally and independently substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁C₄ alkoxy; each of R⁸ and R⁹ is independently —H, halogen,cyano, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄alkoxyalkyl, —O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄alkyl)₂; R¹¹, R¹², R¹³ and R¹⁴ are each independently —H, halogen, orC₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; or optionally, R¹³ and R¹⁴, together with the carbon atomto which they are attached, form a cyclopropane ring, optionallysubstituted with one or more instances of methyl; R²¹, R²², R²³ and R²⁴are each independently —H, halogen, —OH, or C₁-C₆ alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, oxo, hydroxy, oxo, amino,carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁C₆ aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; R⁶ and R⁷ areeach independently —H or C₁-C₆ alkyl optionally substituted with one ormore substitutents selected from the group consisting of halogen, cyano,hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy, or optionally R⁶ and R⁷, together with the carbon atom towhich they are attached, form a cyclopropane ring optionally substitutedwith one or more instances of methyl; R and R′ are each independently —Hor C₁-C₆ alkyl optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy; or optionally R′, together with R⁵ and thenitrogen atom to which they are attached, form a 5-7 memberednon-aromatic heterocycle optionally substituted with one or moreinstances of J^(D1); each J^(D1) is independently selected from thegroup consisting of halogen, cyano, oxo, —R^(a), —OR^(b), —SR^(b),—SOR^(a), —SO₂R^(a), —NHR^(c), —C(O)R^(b), —C(O)OR^(b), —OC(O)R^(b),—NHC(O)R^(b), —C(O)NHR^(c), —NHC(O)NHR^(c), —NHC(O)OR^(b), —OCONHR^(c),—NHC(O)NHC(O)OR^(b), —N(CH₃)R^(c), —N(CH₃)C(O)R^(b), —C(O)N(CH₃)R^(c),—N(CH₃)C(O)NHR^(c), —N(CH₃)C(O)OR^(b), —OCON(CH₃)R^(c), —C(O)NHCO₂R^(b),—C(O)N(CH₃)CO₂R^(b), —N(CH₃)C(O)NHC(O)OR^(b), —NHSO₂R^(b), —SO₂NHR^(b),—SO₂N(CH₃)R^(b), and —N(CH₃)SO₂R^(b); R″ is independently: i) aC₁-C₆-alkyl optionally substituted with one or more substituentsselected independently from the group consisting of halogen, cyano,hydroxyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆ cyanoalkoxy, C₁-C₆ hydroxyalkoxy,and C₂-C₆ alkoxyalkoxy; or ii) a C₃-C₆ carbocyclic group, a 5-6 memberedheteroaryl group, or a phenyl group, each optionally and independentlybeing substituted with one or more substituents independently selectedfrom the group consisting of halogen, cyano, hydroxy, oxo, nitro, —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆cyanoalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkoxyalkyl, C₁-C₆-aminoalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ aminoalkoxy, C₁-C₆cyanoalkoxy,C₁-C₆-hydroxyalkoxy, and C₂-C₆ alkoxyalkoxy; R* is independently: i)—H;ii) a C₁-C₆ alkyl group optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₃-C₈ non-aromaticcarbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 memberedheteroaryl, —O(C₁-C₆ alkyl), and —C(O)(C₁-C₆-alkyl); wherein each ofsaid alkyl groups in —O(C₁-C₆ alkyl), and —C(O)(C₁-C₆-alkyl) isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy;and wherein each of said carbocycle, heterocycle, phenyl, and heteroarylis independently and optionally substituted with one or more instancesof J^(E1); or iii) a C₃-C₈ non-aromatic carbocycle, or a 4-8 memberednon-aromatic heterocycle, each of which is independently and optionallysubstituted with one or more instances of J^(E1); each J^(E1) isindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, amino, carboxy, amido, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and—C(O)(C₁-C₆-alkyl), wherein each of said alkyl groups is optionally andindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, oxo,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄alkyl), CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy; each R^(a) isindependently: i) a C₁-C₆ aliphatic group optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido,—O(C₁-C₆ alkyl), —C(O)(C₁-C₆-alkyl), C₃-C₈ non-aromatic carbocycle, 4-8membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and6-10 membered carbocyclic aryl group; wherein each of said alkyl groupsfor the substituents of the C₁-C₆ aliphatic group represented by R^(a)is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl,and carbocyclic aryl groups for the substituents of the C₁-C₆ aliphaticgroup represented by R^(a) is optionally and independently substitutedwith one or more instances of J^(E1); ii) a C₃-C₈ non-aromaticcarbocycle, or a 4-8 membered non-aromatic heterocycle, each of which isoptionally and independently substituted with one or more instances ofJ^(E1); or iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclicaryl group, each of which is optionally and independently substitutedwith one or more instances of J^(E1); R^(b) and R^(c) are eachindependently R^(a) or —H; or optionally, R^(b) and R^(c), together withthe nitrogen atom(s) to which they are attached, each independently forma 5-7 membered non-aromatic heterocycle optionally substituted with oneor more instances of J^(E1); p and q are each independently 0, 1 or 2; xis 0, 1 or 2; and r is 1 or
 2. 173. The method of claim 172, wherein R⁴is:

wherein: ring E is a C₄-C₈ non-aromatic carbocycle optionally furthersubstituted with one or more instances of J^(A); ring F is a 4-8membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(E1); R⁹ is independently —H, halogen, cyano,hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₂-C₄alkoxyalkyl, —O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄alkyl)₂; R¹¹, R¹², R¹³ and R¹⁴ are each independently —H, halogen, orC₁-C₆ alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano, oxo,hydroxy, oxo, amino, carboxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆aminoalkoxy, C₁-C₆cyanoalkoxy, C₁-C₆ hydroxyalkoxy, and C₂-C₆alkoxyalkoxy; or optionally, R¹³ and R¹⁴, together with the carbon atomto which they are attached, form a cyclopropane ring, optionallysubstituted with one or more instances of methyl; p is 0, 1 or 2; and xis 0, 1 or
 2. 174. The method of claim 172, wherein ring F is selectedfrom any one of rings F1-F6:

wherein each of rings F1-F6 is optionally and independently substitutedwith one or more instances of J^(E1); and each R^(f) is independently —Hor C₁-C₆ alkyl optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, amino, carboxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ cyanoalkoxy, and C₁-C₆ hydroxyalkoxy.
 175. The methodof claim 172, wherein R⁴ is:


176. The method of claim 175, wherein Q² is independently —O—, —CO₂—,—OC(O)—, —C(O)NR—, —NRC(O)—, —NRC(O)NR—, —NRCO₂—, —OC(O)NR—, or—(CR⁶R⁷)_(p)—Y¹—.
 177. The method of claim 176, wherein Q² isindependently —O—or —CO₂—.
 178. The method of claim 175, wherein: R⁵ isindependently i) —H; ii) an optionally substituted C₁-C₆ alkyl group;iii) an optionally substituted C₃-C₇ non-aromatic carbocycle; or iv) a4-7 membered non-aromatic heterocycle optionally substituted with one ormore instances of J^(D1).
 179. The method of claim 175, wherein: R¹ is—H; R² is —H, —CH₃, —CH₂OH, or —NH₂; R³ is —H, —-F, —Cl, C₁-C₄ alkyl, orC₁-C₄ haloalkyl; Z¹ is —H, —F, or —Cl; Z² is —H or C₁-C₆ alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, cyano, hydroxy, and—O(C₁-C₄ alkyl); Z³ is —H or C₁C₆ alkyl optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, hydroxy, and —O(C₁-C₄ alkyl); R⁵ is: i) —H; ii) anoptionally substituted C₁-C₆ alkyl group; iii) an optionally substitutedC₃-C₇ non-aromatic carbocycle; or iv) an optionally substituted 4-7membered non-aromatic heterocycle; or optionally, together with R andthe nitrogen atom to which it is attached, form a 5-7 membered,optionally substituted non-aromatic heterocycle; and said alkyl grouprepresented by R⁵ is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), C₁-C₄alkoxy, an optionally substituted C₃-C₇ non-aromatic carbocycle , anoptionally substituted 4-7 membered non-aromatic heterocycle; andwherein each of said carbocycles and heterocycles represented by R⁵, andreferred to for the substituents of the C₁-C₆ alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄ alkyl), —OC(O)(C₁-C₄alkyl), —C(O)O(C₁C₄ alkyl) and CO₂H, wherein each of said alkyl groupsis optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —O(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄alkoxy.
 180. The compound of claim 175, wherein: R′ is —H; R² is H or—CH₂OH; R³ is —H, —F, or —Cl; Z¹ is —H, —F, or —Cl; Z² is —H; Z³ is —H;R⁵ is independently: i) H or ii) a C₁-C₆-alkyl group optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, cyano, hydroxy, oxo, C₁-C₄ alkyl,—O(C₁-C₄ alkyl), —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —C(O)(C₁-C₄alkyl), —OC(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —CO₂H, C₃-C₇non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl,and 5-6 membered heteroaryl; wherein each of said alkyl groups referredto in the substituents of the C₁-C₆ alkyl group represented by R⁵ isindependently and optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy;and wherein each of said carbocycle, phenyl, heterocycle, and heteroarylreferred to in the substituents of the C₁-C₆ alkyl group represented byR⁵ is independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, oxo, C₁-C₄ alkyl, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), and C₁-C₄ alkoxy.
 181. The method of claim 175, wherein each ofJ^(A) is selected from the group consisting of halogen, cyano, hydroxy,C₁-C₆ alkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)N(C₁-C₄ alkyl)₂,—C(O)(C₁-C₄-alkyl), —OC(O)(C₁-C₄ alkyl), —NHC(O)(C₁-C₄ alkyl), and—N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl); wherein each of said alkyl groups isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, cyano,hydroxy, oxo, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and C₁-C₄ alkoxy.182. The method of claim 181, wherein each of J^(A) is selected from thegroup consisting of halogen, cyano, hydroxy, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄alkyl), C₁-C₄ alkoxy, and C₁-C₄ alkyl optionally substituted with one ormore substituents selected from the group consisting of halogen, cyano,hydroxy, and —O(C₁-C₄ alkyl).
 183. The method of claim 175, wherein: R¹is —H; R² is —H; R³ is —H, —F, or —Cl; Z¹ is —H, —F, or —Cl; Z² is —H;Z³ is —H; R⁵ is —H, or an optionally substituted C₁-C₆ alkyl; each R⁸ isindependently —H, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄hydroxyalkyl, C₂-C₄ alkoxyalkyl, or —O(C₁-C₄ alkyl); each of R⁹, R¹³,and R¹⁴ is independently —H or C₁-C₄ alkyl; R²¹, R²², R²³, an R²⁴ areeach independently —H, halogen, —OH, or C₁-C₆ alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, and —O(C₁-C₆ alkyl); and eachof rings G1-G2 is independently a 5-10 membered non-aromatic bridgedcarbocycle optionally substituted with one or more substituents selectedfrom the group consisting of halogen, cyano, hydroxy, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —O(C₁-C₆ alkyl), C₁-C₄ alkyl that isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, hydroxy, and C₁-C₄ alkoxy.
 184. The methodof claim 175, wherein x is 0 or
 1. 185. The method of claim 175, whereinR³ is methyl or ethyl.
 186. The method of claim 172, wherein thecompound of Formula (IA) is selected from

or a pharmaceutically acceptable salt thereof.